Grants Funded

Grants Funded

 

 

As of June 2013, PRF has provided over $5 million to fund 54 grants for Progeria-related research projects performed in 17 states and 10 other countries! We continue to solicit proposals worldwide and through our scientific workshops, in our continuing effort to encourage researchers to work in this field. All projects are carefully evaluated by our Medical Research Committee and Board of Directors, as we strive to fund research targeted to help us reach our goal of developing treatments and the cure for Progeria. 

Medical Research Grant Application Guidelines

Medical Research Grant Application Guidelines

 Grants We Have Funded and Biological Sketches of the Researchers 

  • June 2013 (start date September 1, 2013): To Dr. Brian Snyder, PhD, : Beth Israel Deaconess Medical Center, Boston, MA.; “Characterization of the Musculoskeletal, Craniofacial and Skin Phenotypes of the G608G Progeria Mouse Model”.
  • June 2013 (start date September 1, 2013): To Dr. Robert Goldman, PhD, : Northwestern University; “New Insights into the Role of Progerin in Cellular Pathology”.
  • June 2013 (start date September 1, 2013): To Dr. Christopher Carroll, PhD, : Yale University, New Haven, CT.; “Regulation of progerin abundance by the inner nuclear membrane protein Man1”.
  • June 2013 (start date September 1, 2013): To Dr. Katharine Ullman,: University of Utah, Salt Lake City, UT; "Elucidating how progerin impacts the role of Nup153 in the DNA damage response”.
  • June 2013 (start date September 1, 2013): To Dr. Katherine Wilson,: Johns Hopkins School of Medicine, Baltimore, MD; “Natural expression of progerin and consequences of reduced lamin A tail O-GlcNAcylation”.
  • June 2013 (start date September 1, 2013): To Dr. Brian Kennedy,: Buck Institute for Research on Aging, Novato, CA; “Small Molecule Aging Intervention in Progeria”.
  • December 2012 (start date August 2013):  To Dr. Gerardo Ferbeyre, PhD, University of Montreal, Montreal, Quebec: “Control of progerin clearance by defarnesylation and phosphorylation at serine 22“
  • December 2012 (start date February 2013): To Dr. Thomas Misteli, PhD, National Cancer Institute NIH, Bethesda, MD: "Small molecule discovery in HGPS"
  • December 2012 (start date April or May 2013): To Karima Djabali, PhD, Technical University of Munich, Munich, Germany: "Progerin dynamics during cell cycle progression"
  • September 2012: To Tom Misteli, PhD, National Cancer Institute, NIH, Bethesda, MD; Technician Award
  • July 2012 (start date September 1, 2012): To Vicente Andrés García, PhD, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; “Quantification of farnesylated progerin and identification of genes that activate aberrant LMNA splicing in Hutchinson-Gilford Progeria Syndrome”
  • July 2012 (start date September 1, 2012): To Dr. Samuel Benchimol, York University, Toronto, Canada: “Involvement of p53 in the premature senescence of HGPS”
  • July 2012: To Tom Misteli, PhD, National Cancer Institute, NIH, Bethesda, MD; Specialty Award Amendment
  • December 2011 (start date March 1, 2012): To Dr. Thomas Dechat, PhD, Medical University of Vienna, Austria; “Stable membrane association of progerin and implications for pRb signaling
  • December 2011 (start date March 1, 2012): To Maria Eriksson,PhD, Karolinska Institute, Sweden; Analyzing the possibility for Progeria disease reversal
  • December 2011 (start date March 1, 2012): To Colin L. Stewart D.Phil, Institute of Medical Biology, Singapore; "Defining themolecular basis to vascular smooth muscle deterioration in Progeria
  • September 2011 (start date January 1, 2012): To Dr. Dylan Taatjes, University of Colorado, Boulder, CO: Comparative metabolic profiling of HGPS cells and evaluation of phenotypic changes upon modulation of key metabolites
  • June 2011 (start date January 1, 2012): to Jan Lammerding, PhD, Cornell University’s Weill Institute for Cell and Molecular Biology, Ithaca, NY; Vascular smooth muscle cell dysfunction in Hutchinson-Gilford Progeria Syndrome 
  • December 2010 (start date April 1, 2011): To Robert D. Goldman, PhD, Northwestern University Medical School, Chicago, IL; A Role for B-type Lamins in Progeria 
  • December 2010: To John Graziotto, PhD,  Massachusetts General Hospital, Boston, MA; Clearance of Progerin Protein as Therapeutic Target in Hutchinson-Gilford Progeria Syndrome
  • December 2010 (Start date April 1, 2011): To Tom Glover PhD, U Michigan, Ann Arbor, MI; “Identifying Genes for Progeria and Premature Aging by Exome Sequencing”
  • December 2010 (start date March 1, 2011): To Yue Zou, PhD, East Tennessee State University, Johnson City, TN; Molecular Mechanisms of Genome Instability in HGPS 
  • December 2010 (start date January 1, 2011): To Kan Cao, PhD, University of Maryland, College Park, MD; Rapamycin Reverses Cellular Phenotype and Enhanced Mutant Protein Clearance in Hutchinson Gilford Progeria Syndrome 
  • June 2010 (start date October 1, 2010): To Evgeny Makarov, PhD, Brunel University, Uxbridge, United Kingdom; Identification of the LMNA Splicing Regulators by Comparative Proteomics of the Spliceosomal Complexes.
  • October 2009:  to Jason D. Lieb, PhD, University of North Carolina, Chapel Hill NC;  Interactions between genes and lamin A/progerin: a window to understanding Progeria pathology and treatment
  • October 2009: To Tom Misteli, PhD, National Cancer Institute, NIH, Bethesda, MD;  Identification of small molecule modulators of LMNA splicing
  • August 2009: to William L. Stanford, PhD, University of Toronto, Canada
    Induced-Pluripotent Stem Cells (iPSC) from HGPS patient fibroblasts to elucidate the molecular mechanism associated with diminishing vascular function
  • July 2009: to Jakub Tolar, University of Minnesota, Minneapolis, MN;
    Correction of human progeria induced pluripotent cells by homologous recombination
  • September 2008 (start date January 2009): To Kris Noel Dahl, PhD, Carnegie Mellon University, Pittsburgh, PA;
    “Quantification of progerin recruitment to membranes”
  • October 2007: To Michael A. Gimbrone, Jr., MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA Endothelial Dysfunction and the Pathobiology of Accelerated Atherosclerosis in Hutchinson-Gilford Progeria Syndrome
  • September 2007 (Start date January 2008): To Bryce M. Paschal, PhD, University of Virginia School of Medicine, Charlottesville, VA; Nuclear Transport in Hutchinson-Guilford Progeria Syndrome
  • May 2007: To Thomas N. Wight, PhD, Benaroya Research Institute, Seattle, WA; The use of a mouse model of HGPS to define the influence of Lamin AD50 expression on vascular extracellular matrix production and the development of vascular disease.
  • March 2007: To Jemima Barrowman, PhD, Johns Hopkins School of Medicine, Baltimore, MD; Fundamental Mechanism of Lamin A Processing: Relevance to the Aging Disorder HGPS 
  • August 2006: To Zhongjun Zhou, PhD, University of Hong Kong, China.  Stem cell therapy of Laminopathy-based Premature Aging
  • August 2006: To Michael Sinensky, PhD, East Tennessee State University, Johnson City, TN;
    Effect of FTIs’ on the Structure and Activity of Progerin
  • June 2006: To Jan Lammerding, PhD, Brigham and Women's Hospital, Cambridge, MA; The role of nuclear mechanics and mechanotransduction in Hutchinson-Gilford Progeria syndrome and the effect of farnesyltransferase inhibitor treatment
  • June 2006:To Tom Misteli, PhD, National Cancer Institute, NIH, Bethesda, MD;
    Molecular Therapy Approaches for HGPS via correction of pre-mRNA Splicing
  • June 2005: To Lucio Comai, PhD, University of Southern California, Los Angeles, CA; Functional Analysis of Hutchinson-Gilford Progeria Syndrome
  • June 2005: To Loren G. Fong, PhD, University of California, Los Angeles, CA;
    New Mouse Models to Study the Cause of Hutchinson-Gilford Progeria Syndrome
  • January 2005: To Dr. Karima Djabali, PhD, Columbia University, New York, NY; Defining progerin dominant negative effects on the nuclear functions in HGPS cells
  • December 2004: To Robert D. Goldman, PhD and Dale Shumaker, PhD, Northwestern University Medical School, Chicago, Illinois
    The Effects of the Major Mutation on Human Lamin A's Function in DNA Replication
  • August 2004 (Start date January 2005): To Stephen Young, PhD, UCLA, Los Angeles, CA; for his project entitled "Genetic Experiments in Mice to Understand Progeria".
  • April 2004: To Monica Mallampalli, Ph D, and Susan Michaelis, PhD, The Johns Hopkins School of Medicine, Baltimore, MD; “Structure, Location and Phenotypic Analysis of Progerin, the mutant form of prelamin A in HGPS”
  • December 2003: To Joan Lemire, PhD, Tufts University School of Medicine, Boston, MA; “Developing a smooth muscle cell model for the study of Hutchinson-Gilford Progeria Syndrome: Is aggrecan a significant component of the phenotype?”
  • December 2003: To W. Ted Brown, MD, PhD, FACMG, The Institute for Basic Research in Developmental Disabilities, Staten Island, NY: “Dominant Negative Mutation Effects of Progerin”
  • September 2003: To Thomas W. Glover, Ph.D., University of Michigan, "
    Role of Lamin A Mutations in Hutchinson-Gilford Progeria Syndrome"
  • May 2002: To Associate Professor Anthony Weiss at the University of Sydney, Australia, Title of project: Candidate Molecular Markers for Hutchinson-Gilford Progeria Syndrome
  • January 2001 (Start date July 2001): To John M. Sedivy, PhD Brown University, Providence, RI; & Junko Oshima, MD, PhD, University of Washington, Seattle, WA, Cloning of the Gene for Hutchinson-Gilford Progeria Syndrome by Somatic Cell Complementation"
  • December 2001 (Start date February 2002): To Thomas W. Glover, Ph.D., University of Michigan, "Genome Maintenance in Hutchinson-Gilford Progeria Syndrome"
  • January 2000: To Leslie B. Gordon, MD, PhD, Tufts University School of Medicine , Boston, MA; "The Role of Hyaluronic Acid in Hutchinson-Gilford Progeria Syndrome"
  • August 1999: To Leslie B. Gordon, MD, PhD, Tufts University School of Medicine , Boston, MA; "The Pathophysiology of Arterioscleros is in Hutchinson-Gilford Progeria Syndrome"

Medical Research Grant Application Guidelines [61.5kb PDF]

Medical Research Grant Application Guideline


June 2013 (start date September 1, 2013): To Dr. Brian Snyder, PhD, : Beth Israel Deaconess Medical Center, Boston, MA.; “Characterization of the Musculoskeletal, Craniofacial and Skin Phenotypes of the G608G Progeria Mouse Model”.

Brian D. Snyder, M.D., Ph.D. is a Board Certified Pediatric Orthopaedic surgeon on staff at Boston Children’s Hospital, where his clinical practice focuses on hip dysplasia and acquired deformities about the hip, spinal deformity, cerebral palsy and pediatric trauma. He is director of the Cerebral Palsy clinic at Boston Children’s Hospital. In addition, he is an Associate Professor of Orthopaedic Surgery, Harvard Medical School and Associate Director of The Center for Advanced Orthopaedic Studies (CAOS) at Beth Israel Deaconess Medical Center (formerly the Orthopaedic Biomechanics Laboratory). The Laboratory is a multi-disciplinary core research facility associated with the Departments of Bioengineering at Harvard University, Massachusetts Institute of Technology, Boston University, Harvard Medical School and the Harvard Combined Orthopaedic Residency Program. Dr. Snyder has merged the sophisticated analytic techniques developed in the Laboratory with the innovative diagnostic and surgical techniques developed at Children’s Hospital for treating musculoskeletal diseases. Dr. Snyder’s group focuses on basic and applied research in musculoskeletal biomechanics including: characterization of bone structure-property relationships; prevention of pathologic fractures as a consequence of metabolic bone diseases and metastatic cancer; biomechanical analysis of mechanisms of spine injury and development of technology to evaluate the biochemical and biomechanical properties of hyaline cartilage in synovial joints. Dr. Snyder will analyze the changes in the axial and appendicular skeleton of the homozygous mouse model of the G609G gene mutation in the LMNA gene that leads to Hutchinson-Gilford Progeria syndrome (HGPS) using the CT based structural rigidity analysis software package that his lab has developed and validated to accurately predict fracture risk in children and adults with benign and malignant bone neoplasms and measure the response of the appendicular skeleton to treatment in children affected by Progeria.

A mouse model of Progeria has been developed at the NIH that has the same musculoskeletal characteristics observed in children with Progeria. To date, there has not been an in depth evaluation of musculoskeletal progeria features in this animal model. Specially, the issue of joint stiffness has also not been evaluated in detail, and It is unclear whether this is a consequence of changes in the skin, muscle, joint capsule, articular cartilage or joint deformity.

We will conduct a thorough evaluation of this mouse model using total body CAT scans of the skeleton and vasculture and the joints. We’ll also conduct biomechanical studies of bone, cartilage and skin to characterize changes (compared to normal animal) in shape of the bone, calcification of the blood vessels, changes in the skull and the skin.

We will also assess the extent that these phenotypic changes are inter-related and whether these changes can be used to track disease severity and the response to treatment. For example are changes in the musculoskeletal system predictive of changes in the vasculature?

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June 2013 (start date September 1, 2013): To Dr. Robert Goldman, PhD, : Northwestern University; “New Insights into the Role of Progerin in Cellular Pathology”.

Robert D. Goldman, PhD, is the Stephen Walter Ranson Professor and Chairman of the Department of Cell and Molecular Biology at Northwestern University Feinberg School of Medicine. He is an authority on the structure and function of the cytoskeletal and nucleoskeletal intermediate filament systems. He and his colleagues have published over 240 scientific articles. His work has led to a number of honors and awards, including an Ellison Foundation Senior Scholar Award in human aging and a MERIT award from the National Institute of General Medical Sciences. Dr. Goldman is a Fellow of the American Association for the Advancement of Science, and served on its board of directors from 1997-2001. He has held numerous positions in the scientific community, including organizing meetings and editing monographs and lab manuals for the Cold Spring Harbor Laboratory and has served on review committees for the American Cancer Society and the NIH. He was President of the American Society for Cell Biology and of the American Association of Anatomy, Cell Biology and Neuroscience Chairpersons. Goldman founded and for many years directed the Science Writers Hands On Fellowship Program at the Marine Biological Laboratory (MBL) and served on the MBL Board of Trustees, as Director of the MBL’s Physiology Course and was Director of the MBL’s Whitman Research Center. He is an Associate Editor of the FASEB Journal, the Molecular Biology of the Cell and Bioarchitecture. He also serves on the Editorial Boards of Aging Cell and Nucleus.

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June 2013 (start date September 1, 2013): To Dr. Christopher Carroll, PhD, : Yale University, New Haven, CT.; “Regulation of progerin abundance by the inner nuclear membrane protein Man1”.

The molecular mechanisms that control the abundance of Lamin A protein are not well understood. We have shown that the inner nuclear membrane protein Man1 prevents the accumulation of Lamin A in human cells. We will determine whether Man1 also acts to limit the accumulation of progerin, the mutant form of Lamin A that causes Hutchison-Gilford Progeria Syndrome (HGPS), and if so, whether this pathway represents a novel target for therapeutics that delay or prevent the accumulation of progerin in children with HGPS.

Topher Carroll was a graduate student in the lab of David Morgan at University of California San Francisco where he studied the enzymology of the anaphase-promoting complex. He then went to Aaron Straight's lab in the Dept. of Biochemistry at Stanford University to explore the epigenetic mechanisms that regulate centromere assembly and propagation. Topher started his own lab in the Dept. of Cell Biology at Yale University in the spring of 2012. His lab is interested in nuclear organization and its relationship to chromatin structure and human disease.


June 2013 (start date September 1, 2013): To Dr. Katharine Ullman,: University of Utah, Salt Lake City, UT; "Elucidating how progerin impacts the role of Nup153 in the DNA damage response”.

Katie Ullman received a BA from Northwestern University and then attended Stanford University for her PhD studies. Following a postdoctoral fellowship at University of California, San Diego, she joined the faculty of the University of Utah in 1998. Katie is a member of the Departments of Oncological Sciences and Biochemistry, as well as an Investigator in the Huntsman Cancer Institute. She is the recipient of a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund and co-leads the Cell Response and Regulation Program in the Cancer Center.

This project aims to gain new insight into the etiology of Hutchinson-Gilford Progeria Syndrome (HGPS) by tackling how mutation in lamin A –which results in expression of a mutated form of lamin A termed progerin–alters the function of the protein Nup153, especially in the context of DNA damage. Nup153 is a component of a large structure called the nuclear pore complex and is recently recognized to participate in the cellular response to DNA damage. Lamin A is known to interact with Nup153 and also participates in the response to DNA damage. We will study this functional intersection, and build on these connections with the goal of rapidly integrating new information into the context of HGPS.

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June 2013 (start date September 1, 2013): To Dr. Katherine Wilson,: Johns Hopkins School of Medicine, Baltimore, MD; “Natural expression of progerin and consequences of reduced lamin A tail O-GlcNAcylation”.

Katherine Wilson, PhD, Katherine L. Wilson grew up in the Pacific Northwest. She studied microbiology in Seattle (BS, University of Washington), biochemistry and genetics in San Francisco (PhD, UCSF) and began exploring nuclear structure as a postdoctoral fellow in San Diego (UCSD). She then joined the faculty at Johns Hopkins University School of Medicine in Baltimore, where she is Professor of Cell Biology. Her lab studies the ‘trio’ of proteins (lamins, LEM-domain proteins and their enigmatic partner, BAF) that form nuclear 'lamina' structure, to understand how mutations in these proteins cause muscular dystrophy, heart disease, lipodystrophy, Hutchinson-Gilford Progeria Syndrome and Nestor-Guillermo Progeria Syndrome.

Progerin has been viewed as an ‘unnatural’ form of lamin A. However new work suggests progerin is expressed at high levels at two specific times and places in the human body—after birth when the newborn heart is being remodeled (closure of the ductus arteriosus), and in cells (fibroblasts) exposed to ultraviolet (UV-A) light. This suggests progerin is a natural gene product that is expressed at specific times, for specific (unknown) reasons. A basic understanding of these proposed ‘natural’ roles of progerin might identify new pathways that could be targeted therapeutically in HGPS. Starting with newborn cow hearts, and UVA-irradiated fibroblasts, this project will purify and identify proteins that associate with progerin, and evaluate their known or potential impact on HGPS. We will also test the possibility that progerin escapes regulation by an essential enzyme (‘OGT’; O-GlcNAc Transferase) that normally ‘tags’ the lamin A tail with many copies of a small sugar (‘GlcNAc’). This project will identify sugar-modified site(s) in lamin A versus progerin, ask if these modifications promote healthy lamin functions, and determine if they are influenced by drugs in HGPS clinical trials.

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June 2013 (start date September 1, 2013): To Dr. Brian Kennedy,: Buck Institute for Research on Aging, Novato, CA; “Small Molecule Aging Intervention in Progeria”.

Brian K. Kennedy, PhD is President and Chief Executive Officer of Buck Institute for Research on Aging He is internationally recognized for his research in the basic biology of aging and as a visionary committed to translating research discoveries into new ways of detecting, preventing and treating age-related conditions. These include Alzheimer’s and Parkinson’s diseases, cancer, stroke, diabetes and heart disease among others. He leads a team of 20 principal investigators at the Buck Institute - all of whom are involved in interdisciplinary research aimed at extending the healthy years of life.

He is actively involved in aging research in the Pacific Rim, which features the largest elderly population in the world. He is a visiting professor at the Aging Research Institute at Guangdong Medical College in China. He is also an Affiliate Professor in the Department of Biochemistry at the University of Washington, Seattle.

Mutations in A-type nuclear lamins give rise to a range of diseases termed laminopathies, which are associated with cardiovascular disease, muscular dystrophy and progeria. Among these are a subset, which affect C-terminal processing lamin A, and give rise to progeroid syndromes that resemble accelerated aging. The question as to whether or not progerias are mechanistically related to the events that drive normal aging has plagued the aging field for decades with respect to both Werner’s and Hutchison-Gilford Progeria syndromes. Small molecules have recently been identified that slow aging (rapamycin) and protect against age-associated chronic diseases (rapamycin and resveratrol). If progeria is linked mechanistically to normal aging, these small molecules and others that are emerging may be effective agents in the treatment of HGPS. In this study, Dr. Kennedy’s lab plans to employ mouse models of progeria to evaluate the efficacy of resveratrol and rapamycin (as well as derivatives of both agents) toward ameliorating disease pathology.

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December 2012 (start date August 2013):  To Dr. Gerardo Ferbeyre, PhD, University of Montreal, Montreal, Quebec: “Control of progerin clearance by defarnesylation and phosphorylation at serine 22“

The accumulation of progerin, an altered form of lamin A, causes the Hutchinson-Gilford Progeria syndrome. The ideal treatment for the disease should prevent the accumulation of progerin by decreasing its synthesis or promoting its degradation. However, little is known about the normal turnover of lamin A or progerin. The accumulation of progerin in nuclear lamina is controlled by farnesylation. We have found that lamin A farnesylation controls its phosphorylation at serine 22, an event previously linked to depolimerazation of the nuclear lamina during mitosis. However, we have found that S22 phosphorylation also occurs during interphase and is associated to the generation of progerin cleavage fragments. We propose a new pathway for progerin turnover that includes defarnesylation and S22 phosphorylation. We think that a molecular understanding of this pathway can leads to novel therapeutic possibilities for progeria. In particular the identification of kinases and phosphatases regulating the phosphorylation of lamin A at serine 22 and proteases mediating lamin A tunover will help to identify drugs that stimulate progerin turnover and improve HGPS patients.

Dr Gerardo Ferbeyre graduated from Medical School at the University of Havana, Cuba in 1987 and has a PhD in biochemistry from the University of Montreal in Canada where he studied ribozymes.  He did postdoctoral training at Cold Spring Harbor Laboratory with Dr. Scott Lowe. There he established a link between the promyelocytic leukemia protein PML and oncogene-induced senescence and studied the role of p53 and p19ARF as mediators of cellular senescence. In October 2001, Dr Ferbeyre joined the Department of biochemistry of the University of Montreal to continue his scientific research on senescence and the possibilities to reactivate the promyelocytic leukemia protein to treat cancers. Recent contributions from his laboratory include the discovery that DNA damage signaling mediates senescence and a link between defects in lamin A expression and senescence.

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December 2012 (start date February 2013): To Dr. Thomas Misteli, PhD, National Cancer Institute NIH, Bethesda, MD: "Small molecule discovery in HGPS"

Dr. Misteli’s team is developing novel therapeutic strategies for Progeria. His group’s work focuses on interfering with the production of the progerin protein using molecular tools and to find novel small molecules to counteract the detrimental effects of progerin in patient cells. These efforts will lead to a detailed cell biological understanding of Progeria cells and will bring us closer to a molecularly targeted therapy for Progeria. 


Tom Misteli is an internationally renowned cell biologist who pioneered the use of imaging approaches to study genomes and gene expression in living cells. He is a Senior Investigator and Associate Director at the National Cancer Institute, NIH. His laboratory’s interest is to uncover fundamental principles of spatial genome organization and to apply this knowledge to the development of novel diagnostic and therapeutic strategies for cancer and aging. He has received numerous awards including the Gold Medal of the Charles University, the Flemming Award, the Gian-Tondury Prize, the NIH Director’s Award, and an NIH Merit Award. He acts as an advisor for numerous national and international agencies and serves on several editorial boards including Cell. He is the Editor-in-Chief of The Journal of Cell Biology and of Current Opinion in Cell Biology.


December 2012 (start date April or May 2013): To Karima Djabali, PhD, Technical University of Munich, Munich, Germany: "Progerin dynamics during cell cycle progression"

Hutchinson-Gilford progeria syndrome (HGPS) is caused by mutations in the lamin A gene, which results in the production and accumulation of a mutant prelamin A protein termed progerin. Because this protein accumulates and interferes with nuclear components and functions, identifying progerin direct effectors during mitosis and differentiation is crucial for understanding how and when progerin triggers the nuclear defects that lead cells to premature senesce.

In this study Dr. Djabali lab’s plans to identify progerin direct effectors within the nuclear scaffold, nuclear envelope, and nuclear interior to determine the initial molecular interactions that are disrupted by progerin expression. Toward this end, they will use anti-progerin antibodies and HGPS cellular models, including fibroblasts and skin derived-precursor cells established from skin biopsies derived from patients with HGPS (PRF Cell Bank). They will combine biochemical and cellular imaging to identify progerin effectors and investigate their contribution to the molecular events leading to the typical phenotypic changes observed in HGPS cells that are responsible for the development of HGPS disease. Insights gained from these studies will permit the identification of new therapeutic targets for HGPS treatment and new cellular endpoints for testing the efficacy of potential interventions. We hope that our work will provide the knowledge necessary to bring us and other teams in the HGPS field closer to finding a cure(s) that will help children with HGPS live a longer healthy life.

Karima Djabali, PhD, is Professor of Epigenetics of Aging, Faculty of Medicine, Department of Dermatology and Institute for Medical Engineering (IMETUM) at the Technical University of Munich Germany. Dr. Djabali received her MSc and PhD in Biochemistry at the University Paris VII. She performed her thesis work at the College de France (Prof. F. Gros lab, France) and at the Rockefeller University (Prof. G. Blobel lab, USA). She carried out her postdoctoral research at EMBL (Heidelberg, Germany). She received a Chargé de recherche position at the National Centre for Scientific Research (CNRS, France) in 1994 and served as an associate research scientist in the Department of Dermatology, Columbia University of New York (USA) from 1999 to 2003. Thereafter, Dr Djabali served as an assistant professor in the Department of Dermatology at Columbia University of New York (USA) from 2004 to 2009. Dr. Djabali’s research centers around cellular aging in normal and disease states, with a particular focus on the molecular and cellular pathogenesis of premature aging diseases, such as Hutchinson-Gilford progeria syndrome (HGPS). Her research combines molecular biology, cellular biology, genetics, and proteomics to identify signaling pathways associated with cellular aging to develop preventive strategies to delay and/or correct aging processes.

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September 2012: To Tom Misteli, PhD, National Cancer Institute, NIH, Bethesda, MD; Technician Award

Dr. Misteli's laboratory seeks to identify lead compounds for HGPS drug development by screening of large libraries of chemical molecules. The Specialty Award was used to purchase robotic laboratory equipment required for these studies.

Tom Misteli is an internationally renowned cell biologist who pioneered the use of imaging approaches to study genomes and gene expression in living cells. He is a Senior Investigator and Associate Director at the National Cancer Institute, NIH. His laboratory’s interest is to uncover fundamental principles of spatial genome organization and to apply this knowledge to the development of novel diagnostic and therapeutic strategies for cancer and aging. He has received numerous awards including the Gold Medal of the Charles University, the Flemming Award, the Gian-Tondury Prize, the NIH Director’s Award, and an NIH Merit Award. He acts as an advisor for numerous national and international agencies and serves on several editorial boards including Cell. He is the Editor-in-Chief of The Journal of Cell Biology and of Current Opinion in Cell Biology.

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July 2012 (start date September 1, 2012): To Vicente Andrés García, PhD, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; “Quantification of farnesylated progerin and identification of genes that activate aberrant LMNA splicing in Hutchinson-Gilford Progeria Syndrome”

Hutchinson-Gilford progeria syndrome (HGPS) is a rare fatal genetic disorder characterized by premature aging and death at an average age of 13 years. Most HGPS patients carry a mutation in the LMNA gene (encoding mainly lamin A and lamin C) that leads to the production of ‘progerin’, an abnormal protein that retains a toxic farnesyl modification. Experiments with cell and mouse models of HGPS have conclusively demonstrated that the total amount of farnesylated progerin and the ratio of progerin to mature lamin A determine disease severity in progeria and is a key factor for lifespan. Ongoing clinical trials are therefore evaluating the efficacy of drugs that inhibit progerin farnesylation in HGPS patients. The main objective of this project is to develop a method to routinely and accurately quantify progerin expression and its level of farnesylation, and the ratio of progerin to mature lamin A, in cells from HGPS patients. Measurement of these parameters will help assess the effectiveness of drugs targeting progerin farnesylation, as well as that of future strategies devised to inhibit abnormal processing (splicing) of the LMNA mRNA, the cause of HGPS in most patients. A secondary objective is to perform pilot studies for the development of a high-throughput strategy to identify mechanisms that activate aberrant LMNA splicing.

Vicente Andrés obtained his PhD in Biological Sciences from the University of Barcelona (1990). During postdoctoral training at the Children's Hospital, Harvard University (1991-1994) and the St. Elizabeth's Medical Center, Tufts University (1994-1995), he led studies into the role of homeobox and MEF2 transcription factors in processes of cellular differentiation and proliferation; and it was also during this period that he developed an interest in cardiovascular research.  His career as an independent research scientist began in 1995 when he was appointed Assistant Professor of Medicine at Tufts. Since then Dr. Andrés and his group have studied vascular remodeling during atherosclerosis and post-angioplasty restenosis, and more recently they investigate the role of the nuclear envelope in the regulation of signal transduction, gene expression and cell-cycle activity in cardiovascular disease and aging, with particular emphasis on A-type lamins and Hutchinson-Gilford progeria syndrome (HGPS).

After obtaining a position as a Tenured Research Scientist in the Spanish National Research Council (CSIC), Dr. Andrés returned to Spain in 1999 to establish his research group in the Institute of Biomedicine of Valencia, where he worked as a Full Professor. Since 2006, his group has been a member of the Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares (RECAVA). He joined the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in September 2009. In 2010 he was awarded the Doctor Leon Dumont Prize by the Belgian Society of Cardiology.

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July 2012 (start date September 1, 2012): To Dr. Samuel Benchimol, York University, Toronto, Canada: “Involvement of p53 in the premature senescence of HGPS”

Dr. Benchimol has a long record of accomplishment in the area of p53 function.  He will use his expertise to build upon intriguing preliminary data and test novel hypotheses regarding the role of p53 in mediating the premature senescence shown by cells from Hutchinson-Gilford Progeria syndrome (HGPS) patients.  The first aim is designed to test the hypothesis that progerin causes replication stress, which in turn elicits a senescence growth arrest, and that p53 acts downstream of the progerin-induced replication stress.  This aim is followed by a more mechanistic aim that is designed to determine how progerin and p53 collaborate to elicit a senescence response.

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July 2012: To Tom Misteli, PhD, National Cancer Institute, NIH, Bethesda, MD; Specialty Award Amendment

Dr. Misteli's laboratory seeks to identify lead compounds for HGPS drug development by screening of large libraries of chemical molecules. The Specialty Award was used to purchase robotic laboratory equipment required for these studies.

Tom Misteli is an internationally renowned cell biologist who pioneered the use of imaging approaches to study genomes and gene expression in living cells. He is a Senior Investigator and Associate Director at the National Cancer Institute, NIH. His laboratory’s interest is to uncover fundamental principles of spatial genome organization and to apply this knowledge to the development of novel diagnostic and therapeutic strategies for cancer and aging. He has received numerous awards including the Gold Medal of the Charles University, the Flemming Award, the Gian-Tondury Prize, the NIH Director’s Award, and an NIH Merit Award. He acts as an advisor for numerous national and international agencies and serves on several editorial boards including Cell. He is the Editor-in-Chief of The Journal of Cell Biology and of Current Opinion in Cell Biology.

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December 2011 (start date March 1, 2012): To Dr. Thomas Dechat, PhD, Medical University of Vienna, Austria; “Stable membrane association of progerin and implications for pRb signaling

A-type lamins are important structural proteins of the nucleus in mammalian cells. They are the major components of a filamentous meshwork located at the inner surface of the nuclear envelope and provide not only shape and mechanical stability to the nucleus, but are also involved in essential cellular processes such as DNA replication and gene expression. Beside their localization at the nuclear periphery, an additional more dynamic pool of A-type lamins is present within the nuclear interior, which is suggested to be important for proper cell proliferation and differentiation. In the last thirteen years over 300 mutations in the gene encoding A-type lamins have been associated with various human diseases, including the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS). The molecular disease mechanisms are still poorly understood hampering the development of effective therapeutic strategies. The mutation in the A-type lamin gene associated with HGPS results in the production of a mutant lamin A protein, termed progerin. In contrast to normal lamin A, progerin is stably anchored to the nuclear membrane, which alters the mechanical properties of the nucleus. Our working hypothesis proposes that the membrane-anchored progerin also severely affects the dynamic pool of lamins within the nuclear interior and thus cell proliferation and differentiation.

One aim of this project is to identify the mechanisms responsible for anchoring progerin to the nuclear membrane and to find ways to specifically inhibit this membrane anchorage with the prospect of rescuing the dynamic lamin pool and thereby reverting cellular phenotypes associated with HGPS. Previous findings show that this dynamic pool of lamin in a complex with other proteins regulates cell proliferation via the retinoblastoma protein (pRb) pathway. In support of our hypothesis, it was recently shown that in cells from HGPS patients the pRb pathway is indeed impaired. In the second aim of our project we propose to study the effects of progerin on the regulation, dynamics and activities of the mobile, nucleoplasmic lamin A pool and its associated proteins and its impact on pRb signaling at molecular detail. The results of our study are expected to shed light on the disease-causing molecular mechanisms behind HGPS and may help to identify novel drug targets and drugs for more efficient and targeted therapies. 

Dr. Dechat received his MSc and PhD in Biochemistry at the University of Vienna, Austria. After a year as PostDoc at the Neuromuscular Research Department of the Medical University of Vienna, he was a PostDoc in the laboratory of Prof. Robert Goldman, Northwestern University, Feinberg Medical School, Chicago, Illinois from 2004-2009, working on the structural and functional characterization of nuclear lamins in health and disease with a main focus on the mechanisms leading to Hutchinson-Gilford Progeria Syndrome due to the expression of progerin. Since 2010 he has been an Assistant Professor at the Max F. Perutz Laboratories, Medical University of Vienna, studying the structural and functional properties of nucleoplasmic A-type lamins and LAP2 during the cell cycle and in various diseases associated with mutations in lamins A/C and LAP2.   

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December 2011 (start date March 1, 2012): to Maria Eriksson,PhD, Karolinska Institute, Sweden; Analyzing the possibility for Progeriadisease reversal

In this study Dr. Eriksson's lab plans to usetheir recently developed model for progeria with expression of the most commonLMNA gene mutation in the bone. They have previously shown that suppression ofthe expression of the progeria mutation after progeria skin disease developmentled to an almost complete reversal of the disease phenotype (Sagelius, Rosengardtenet al. 2008). Progeria disease progression will be monitored in the bone tissueat different time points following inhibition of the mutation to analyze thepossibility for disease reversal. Their preliminary results indicate improvedclinical symptoms and give promise towards identifying a possible treatment andcure for this disease.

Dr. Eriksson received her MSc Molecular biology at Umeå University, Sweden in1996, and her PhD in Neurology from the Karolinska Institutet in 2001. She wasa postdoctoral fellow at the National Human Genome Research Institute, NationalInstitutes of Health 2001-2003, and has been a PI/Research group leader andAssistant professor at the Dept of Biosciences and Nutrition at the KarolinskaInstitute since 2003. She is also Associate Professor in Medical Genetics atthe Karolinska Institute. Her research interests include Progeria and geneticmechanisms of aging.

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December 2011 (start date March 1, 2012): To Colin L. Stewart D.Phil, Institute of Medical Biology, Singapore; "Defining themolecular basis to vascular smooth muscle deterioration in Progeria

Children with Progeria die from cardiovascular disease, either a heart attack or stroke. Over the past decade it has become apparent that a key tissue affected by Progeria is the child's blood vessels. Progeria appears to weaken the muscular wall of the blood vessels by somehow causing the smooth muscle cells to die. This not only may make the vessels more fragile, but also stimulates plaque formation leading to blockage of the vessel.  Both outcomes result in the blood vessels failing and, if this is in the heart vessels, this will result in a heart attack.

Colin Stewart and his colleague Oliver Dreesen plan to study how the defective form of the nuclear protein Lamin A (progerin) specificallyaffects the growth and survival of the smooth muscle cells in blood vessels.  Using stem cell technology Colin and colleagues were able to derive stem cells from skin cells established from 2 children with Progeria. These patient specific stem cells they were then turned into smooth muscle cells resembling those from blood vessels. Intriguingly these smooth muscle cells produced some of the highest levels of progerin, compared to other cell types, suggesting a possible reason as to why blood vessels are severely affected in Progeria. Smooth muscle cells with progerin showed evidence of damage to the DNA in the cell's nucleus. Colin and Oliver will use these and other cells derived from the stem cells to understand what type of DNA is damaged and what biochemical processes, necessary for the survival of the smooth muscle cells are affected by progerin. By being able to directly study smooth muscle cells recreated from children with Progeria, they hope to identify exactly what goes wrong with the cells so as to develop novel procedures to test new drugs that may eventually help treat affected children.

Colin Stewart received his D. Phil from the University of Oxford where he studied interactions between teratocarcinomas, the forerunners of ES cells, and early mouse embryos. Following postdoctoral work with Rudolf Jaenisch in Hamburg, he was a staff scientist at EMBL in Heidelberg. There he was instrumental in discovering the role of the cytokine LIF in maintaining mouse ES cells. He also initiated his interest in the nuclear lamins and nuclear architecture in development. He continued his studies on the lamins, stem cells and genomic imprinting following relocation to the Roche Institute of Molecular Biology in New Jersey. In 1996 he moved to the ABL research program in Frederick, Maryland and in 1999 was appointed Chief of theLaboratory of Cancer and Developmental Biology at the National Cancer Institute.In the last decade his interests have focused on the functional architecture ofthe cell's nucleus in stem cells, regeneration, aging and disease, particularlywith regard to how the nuclear functions are integrated with cytoskeletal dynamics in development and disease. Since June 2007 he has been senior principal investigator and assistant director at the Institute of MedicalBiology at the Singapore Biopolis.

Oliver Dreesen is currently a Senior Research Fellow at the Institute of Medical Biology in Singapore. After completing his undergraduate degree in Bern, Switzerland, Oliver held research positions at the Pasteur Institute in Paris and the University of California, San Diego. Hereceived his PhD from The Rockefeller University in New York where he studied the structure and function of chromosome ends (telomeres) during antigenic variation in African Trypanosomes. His current research interests focus on the roleof telomeres in human disease, aging and cellular reprogramming.

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September 2011 (start date January 1, 2012): To Dr. Dylan Taatjes, University of Colorado, Boulder, CO: Comparative metabolic profiling of HGPS cells and evaluation of phenotypic changes upon modulation of key metabolites

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare and debilitating disease that is caused by mutation in the lamin A protein.  Past studies have identified the mutations in lamin A that cause the disease and have evaluated its aberrant function in human cells and in mouse models of HGPS.  This information, coupled with genome-wide expression studies comparing HGPS cells with those from unaffected individuals, has dramatically advanced our understanding of this disease.  One area that has been neglected in HGPS research is a thorough analysis of the metabolic changes that occur in HGPS cells relative to healthy controls.  Metabolic abnormalities accompany many human diseases (e.g. atherosclerosis, diabetes, and cancer), and clinical evaluation of HGPS suggests chronic abnormalities in basic metabolic pathways. 

Cellular metabolites represent the biochemicals that—together with proteins and nucleic acids—comprise the entire repertoire of molecules within a cell.  As such, metabolic changes are arguably as important as gene expression changes in disease pathogenesis.  Indeed, the burgeoning field of “metabolomics” has already yielded many key discoveries linking single metabolites to specific human diseases, including leukemia and metastatic prostate cancer.  Therefore, identification of the metabolites and metabolic pathways that are altered in HGPS should provide insight into disease pathogenesis and may uncover entirely new therapeutic strategies.  This is especially germane to HGPS, as numerous cell-based and in vivo studies have demonstrated that lamin A mutations do not cause irreversible damage and that cellular HGPS phenotypes, if properly treated, can actually be eliminated.

Upon completing a comprehensive, comparative screen of the metabolites present in cells derived from healthy donors and HGPS patients, follow-up biochemical and cell-based assays will establish whether key metabolites identified in the screen can induce HGPS phenotypes in healthy cells, or reverse HGPS phenotypes in diseased cells.  Consequently, this study will not only reveal how HGPS-associated lamin A mutations affect global metabolic pathways in human cells, it will also begin to evaluate whether targeting these pathways represents an effective approach for therapeutic intervention.

The Taatjes lab combines expertise in biochemistry, proteomics, and cryo-electron microscopy to study the fundamental mechanisms that regulate human gene expression.  The lab also implements genome-wide and metabolomics approaches to help link mechanistic findings with physiological consequences.  Metabolomics studies in the Taatjes lab, in conjunction with mechanistic studies with a p53 isoform that causes accelerated aging, serve as a basis for this HGPS study.

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June 2011 (start date January 1, 2012): to Jan Lammerding, PhD, Cornell University’s Weill Institute for Cell and Molecular Biology, Ithaca, NY; Vascular smooth muscle cell dysfunction in Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is caused by mutations in the gene encoding lamins A and C.  Children with HGPS develop hair loss, bone defects, loss of fat tissue, and other signs of accelerated aging before succumbing to stroke or myocardial infarctions in their early teens. Post-mortem studies reveal a dramatic loss of vascular smooth muscle cells in the larger blood vessels of HGPS patients. Vascular smooth muscle cells are critical for the normal function of blood vessels, and loss of vascular smooth muscle cells may constitute the driving force behind the lethal cardiovascular disease in HGPS.

We have previously demonstrated that skin cells from HGPS patients are more sensitive to mechanical stress, resulting in increased cell death when subjected to repetitive stretch. In this project, we will test whether an increased sensitivity to mechanical stress is also responsible for the progressive loss of vascular smooth muscle cells in HGPS, as large blood vessels are exposed to repetitive vessel strain with each heartbeat. Combined with impaired replenishment of the damaged cells, the increased mechanical sensitivity could lead to the progressive loss of vascular smooth muscle cells and the development of cardiovascular disease in HGPS.

To study the effect of mechanical stress on vascular smooth muscle cells in vivo, we will use surgical procedures to locally increase blood pressure or to create vascular injuries in large blood vessels and then compare the effect on survival and regeneration of vascular smooth muscle cells in in a mouse model of HGPS and in healthy controls. Insights gained from these studies will yield new information on the molecular mechanisms underlying the cardiovascular disease in HGPS and may offer new clues into the development of therapeutic approaches.

Dr. Lammerding is an Assistant Professor at Cornell University in the Department of Biomedical Engineering and the Weill Institute for Cell and Molecular Biology. Before moving to Cornell University in 2011, Dr. Lammerding worked as an Assistant Professor in the Department of Medicine at Harvard Medical School/Brigham and Women’s Hospital and served as a Lecturer at the Massachusetts Institute of Technology. The Lammerding laboratory is studying subcellular biomechanics and the cellular signaling response to mechanical stimulation, with a particular focus on how mutations in nuclear envelope proteins such as lamins can render cells more sensitive to mechanical stress and affect their mechanotransduction signaling. Insights gained from this work can lead to a better understanding of the molecular mechanism underlying various laminopathies, a diverse group of diseases including Hutchison-Gilford progeria syndrome, Emery-Dreifuss muscular dystrophy and familial partial lipodystrophy.

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December 2010 (start date April 1, 2011): To Robert D. Goldman, PhD, Northwestern University Medical School, Chicago, IL; A Role for B-type Lamins in Progeria

The A and B-type nuclear lamins are proteins located within the cell’s nucleus. These proteins form separate, but interacting structural networks within the nucleus. The lamins are essential for determining the size, shape, and mechanical properties of the nucleus; and they provide an intranuclear scaffold for organizing chromosomes. We have discovered that when one lamin network is altered by a mutation leading to a malfunction, the other is also altered. Although the typical and atypical forms of Hutchinson Gilford Progeria Syndrome are caused by different mutations in the nuclear lamin A gene, we have found that the B-type lamin networks in progeria patients’ cells are also abnormally altered. The B-type lamins are expressed in all somatic cells from fertilization onward, and they are known to be important in regulating many nuclear functions including DNA replication and gene transcription. Yet little attention has been paid to the lamin B isoforms and their roles in progeria. In this proposal our goal is to determine the effects of the expression of progerin, the most frequently encountered mutant form of lamin A, and other atypical progeria lamin A mutations on the expression, structure and function of the B-type lamins. Our preliminary studies suggest that changes in the B-type lamin networks are important mediators of the cellular pathology in HGPS, because of their interactions with A-type lamins. We will examine changes in the B-type lamins in progeria patient cells and their relationships to cell growth defects and premature senescence. We will also investigate the effects of farnesyltransferase inhibition on the expression, modification and stability of the B-type lamins. This is important as B-type lamins are normally stably farnesylated. These proposed studies are particularly timely given the ongoing clinical trials involving progeria patients utilizing drugs that inhibit protein farnesylation. Our studies promise to provide new insights into the molecular mechanisms responsible for the premature aging of cells in patients with this devastating disease. The results of our investigations should reveal insights into additional potential targets to consider in the development of new therapies for HGPS patients.

Robert D. Goldman, PhD, is the Stephen Walter Ranson Professor and Chairman of the Department of Cell and Molecular Biology at Northwestern University’s Feinberg School of Medicine in Chicago.  Dr. Goldman received his PhD in biology from Princeton University and carried out postdoctoral research at the University of London and at the MRC Institute of Virology in Glasgow.  He served on the faculties of Case Western Reserve University, Carnegie-Mellon University and was a Visiting Scientist at the Cold Spring Harbor Laboratory prior to joining Northwestern.  He is widely recognized as an authority on the structure and function of the nucleoskeletal and cytoskeletal intermediate filament systems.  In the early 1980s he became fascinated with the discovery that lamins were the nuclear form of intermediate filaments.  Since that time, his research laboratory has shown that the nuclear lamins are determinants of the size and shape of the nucleus and that they are critically important factors in the disassembly and reassembly of the nucleus during cell division. His research group has further demonstrated that the lamins assemble into a molecular scaffold within the cell’s nucleus required for DNA replication, transcription and chromatin organization.  In recent years his interest in the lamins has focused on the impact of lamin A mutations that give rise to the premature aging disease Hutchinson Gilford Progeria Syndrome and other atypical forms of progeria.  This has led his research into determining the roles of lamins in chromosome organization, in regulating the epigenetic modifications of chromatin and in cell proliferation and senescence.

Dr. Goldman is a Fellow of the American Association for the Advancement of Science (AAAS), and has been the recipient of Ellison Medical Foundation Senior Scholar and NIH MERIT Awards. He is a prolific writer, has edited numerous volumes for the Cold Spring Harbor Laboratory Press and serves as Associate Editor for the FASEB Journal and Molecular Biology of the Cell. He has been elected to numerous positions in scientific societies including the Board of Directors of the AAAS, the Council and President of the American Society for Cell Biology, and was President of the American Association of Anatomy, Cell Biology and Neuroscience Chairs. He has served on numerous review committees for the American Cancer Society and the NIH, is Director of the Whitman Center of the Marine Biological Laboratory and is frequently invited to organize and speak at international meetings both here and abroad.

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December 2010: To John Graziotto, PhD,  Massachusetts General Hospital, Boston, MA; Clearance of Progerin Protein as Therapeutic Target in Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by a mutation in the lamin A gene, which results in the production and accumulation of the mutant disease protein termed progerin.  Since this protein accumulates, determining how it is degraded is important from a therapeutic standpoint.  The focus of this work is to determine the cellular clearance pathways responsible for degrading the progerin protein.  Using this information, we hope to be able to manipulate those pathways to facilitate progerin clearance, with the goal of enhancing current or future therapies for HGPS. 

Dr. Graziotto is a Postdoctoral Fellow in the Department of Neurology at Massachusetts General Hospital.  He is currently working in the laboratory of Dr. Dimitri Krainc.  A major focus of the lab is the study of neurodegenerative disorders in which mutant proteins accumulate and form aggregates.  The laboratory studies the clearance mechanisms of these proteins in order to identify modifiers of these pathways which could lead to future targets for treatment. 

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 December 2010 (Start date April 1, 2011): To Tom Glover PhD, U Michigan, Ann Arbor, MI; “Identifying Genes for Progeria and Premature Aging by Exome Sequencing”.

“Progeria” describes a number of disorders which exhibit different aspects of premature aging or segmental progeria.  These include HGPS and MAD, both with LMNA mutations, and the DNA repair disorders Cockayne and Werner syndromes.  In addition, there are a number of cases of “atypical” progeria with overlapping but distinct features.  PRF has collected cell lines and/or DNA on 12 such cases of atypical progeria, representing the largest cohort ever assembled.  DNAs have been examined for LMNA exon mutations and none were found, and they are currently being tested for ZMPSTE mutations in Dr.Glover’s lab. In addition, they have phenotypes distinct from classic Werner and Cockayne syndromes.  Therefore, these individuals have mutations in unique progeria genes.   Since most such cases are sporadic, this has been a daunting task.  However, during the last few years enormous technical progress has been achieved in the area of DNA sequencing.  Whole genome exon sequencing, or “exome sequencing”, has been successfully used to identify mutant genes for a number of monogenic traits including, Miller syndrome, Kabuki syndrome, non-specific mental retardation, Perrault syndrome and many others, with numerous other studies in progress including many studies of de novo mutations.  This is a powerful tool for gene identification and it is predicted that in the next few years, we will understand the genetic cause of most monogenic traits. 

In view of these technological advances and the availability of similar patients, Dr. Glover hypothesizes that mutations responsible for atypical progeria can be identified by whole exome sequencing of these patient samples.  Identifying these mutations is essential to understanding disease etiology, developing effective treatments and in developing knowledge of intersecting and interacting molecular and cellular pathways in the progerias and normal aging.  However, this is challenging given that these are apparently all de novo mutations and the phenotypes are heterogeneous. The immediate outcome of this study will be the discovery of 7-15 novel, likely deleterious mutations for each family that are shared by affected family members and may be unique to the family. The joint analysis of these genes across 6-12 families may well reveal instances of distinct deleterious alleles of the same gene, or different defects in the same functional pathway, appearing in multiple families, thus providing the first glimpse of new candidate genes/pathways for progeria.    If successful, the impact of findings could be great and be directly relevant not only to the affected patient and, because of overlapping features, to other forms of progeria including HGPS as well as to normal aging.

Dr. Glover is a Professor in the Department of Human Genetics and Pediatrics at the University of Michigan.  He is the author of over 120 research publications and book chapters.  Dr. Glover has been actively involved in Progeria research for over a decade and has been a member of the PRF Medical Research Committee since its inception in 2004.  His laboratory was involved in the research efforts that first identified LMNA gene mutations in HGPS and in demonstrating that farnyslyation inhibitors can reverse nuclear abnormalities of HGPS cells, opening the door to clinical trials.  A major interest of his laboratory is the mechanisms and consequences of genome instability in human genetic disease.  Current effort s are aimed at understanding the molecular mechanisms involved in producing copy number variant (CNV) mutations in the human genome.  These are a common yet only recently recognized form of mutation important in normal human variation and numerous genetic diseases.  However, unlike other forms of mutation, it is not fully understood how they are formed and the genetic and environmental risk factors involved. 

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December 2010 (start date March 1, 2011): To Yue Zou, PhD, East Tennessee State University, Johnson City, TN; Molecular Mechanisms of Genome Instability in HGPS

The objective of this project is to define the molecular basis of replication abnormality and genome instability in Hutchinson-Gilford progeria syndrome (HGPS) cells. HGPS is a dominant premature aging disease and patients of the disease have an average lifespan of only 13 years. The disease is caused by a point mutation at 1822 or 1824 in exon 11 of lamin A gene, which results in sporadic production of a lamin A mutant protein with 50 amino acids internally truncated, called progerin. Lamin A is a major inner component of the nuclear envelope and skeleton of cells and the presence of progerin leads to abnormal nuclear morphology and genome instability in HGPS cells. Interestingly, recent studies showed that progerin is also produced in normal aging individuals and its level appears to increase with age by an average of 3% per year in coronary arteries. This increase is in concordance with many aspects of cardiovascular pathology in both HGPS and geriatric patients, implicating a potentially important role of progerin in aging and aging-related diseases such cancer and cardiovascular diseases.

While the genetic cause of HGPS is known, the molecular mechanisms by which the action of progerin leads to premature aging-associated phenotypes remain far from clear. We and others have recently demonstrated that HGPS has a phenotype of genome instability caused by cellular accumulation of DNA double-strand breaks (DSBs). DSB accumulation is also a common cause of systemic aging. We also found that Xeroderma Pigmentosum group A (XPA) mislocalizes to DSB sites in HGPS cells, leading to inhibition of DSB repair. Depletion of XPA in HGPS cells partially restores DSB repair. Based on these findings, we hypothesize that the DNA damage accumulation in HGPS is likely due to aberrant activities at replication forks which generate unrepairable DSBs, leading to early replication arrest or replicative senescence. Given the fact that HPGS cells are characterized with early replication arrest and premature replicative senescence, revealing the mechanisms underlying the defective activities at replication forks may hold a key to understand the causes of HGPS phenotypes. The understanding could lead to novel strategies for treatment of the disease by intervening in the disease-causing molecular pathways. On the other hand, it is well known that HGPS patients appear to be cancer-free. Although the mechanism remains unknown, it may be attributed to the premature replicative senescence of HPGS. In this research project, we will determine the molecular basis of DSB accumulation in HGPS with the focus on understanding how DNA damage is produced at replication forks. Next we will determine if progerin interacts with DNA replication factors and how the interaction causes the replication abnormalities.

Dr. Zou is a professor in the Department of Biochemistry and Molecular Biology of Quillen College of Medicine at East Tennessee State University. He received his PhD in Biophysics in 1991 from Clark University. Dr. Zou’s research has mainly focused on understanding the genome instability in cancer and related pathways including DNA repair and DNA damage checkpoints. He has recently become interested in genome instability and DNA damage responses in progeria caused by defective maturation of prelamin A, particularly Hutchinson-Gilford Progeria Syndrome, and his group has made interesting findings on the molecular mechanisms of genome instability in HGPS.

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December 2010 (start date January 1, 2011): To Kan Cao, PhD, University of Maryland, College Park, MD; Rapamycin Reverses Cellular Phenotype and Enhanced Mutant Protein Clearance in Hutchinson Gilford Progeria Syndrome

Dr. Cao’s work will investigate the effect of Everolimus on HGPS cells, alone or in combination with Lanafarnib. This study will allow the evaluation of both the therapeutic potential and the mechanistic basis for such combinatorial therapeutic approach. 

Dr. Cao is an Assistant Professor in the Department of Cell Biology and Molecular Genetics at the University of Maryland.  Dr. Cao’s lab is interested in studying cellular mechanisms in progeria and normal aging.

 


June 2010 (start date October 1, 2010): To Evgeny Makarov, PhD, Brunel University, Uxbridge, United Kingdom; Identification of the LMNA Splicing Regulators by Comparative Proteomics of the Spliceosomal Complexes.

Dr. Makarov’s research interests are in the field of precursor messenger RNA (pre-mRNA) splicing. Pre-mRNA splicing is a cellular process in which non-coding sequences (introns) are removed and coding sequences (exons) are joined together to generate mRNA for protein production. Pre-mRNA splicing is somewhat similar to film editing: if it is not done properly, two unmatched scenes may be stitched together in one episode, which would not make sense. In splicing, if exon-intron boundaries (splice sites) are not correctly identified, the wrong mRNA will be produced. From this a faulty protein will be synthesised and this may cause disease. To extend the analogy, a film scenario is dramatically changed by the selection of scenes; by the same token, in a living cell, pre-mRNA can be processed in different ways via the alternative use of different splice sites. This phenomenon is called alternative splicing and allows the production of several proteins from a single gene. Dr. Makarov is currently focused on the study of disease-associated alternative splicing. The major ongoing project is on the study of the ageing-related pre-mRNA splicing of human LMNA gene, encoding lamin A and C proteins, and especially, its aberrant splicing that causes the premature ageing of Hutchinson Gilford Progeria Syndrome patients. The aim is to identify the proteins modulating the specific splicing outcomes which, in turn, are likely to affect the speed of the ageing process. In this respect, the pharmaceutical targeting of the proteins identified in the proposed research -- inhibition of their function by small interacting molecules -- may lead to the discovery of novel drugs capable of slowing the ageing process. The other ongoing projects are: (i) The study of SCLC (small cell lung cancer) associated alternative splicing of actinine-4 pre-mRNA; (ii) The hTERT alternative splicing regulation as a potential cancer therapeutic modality.

Dr. Makarov was born and grew up in Leningrad, USSR, where he also graduated from the Leningrad Polytechnical University, Department of Biophysics, in 1980.  He earned his Ph.D. degree in Molecular Biology from the Leningrad Nuclear Physics Institute, Department of Molecular and Radiation Biophysics, USSR in 1986 for the study of molecular mechanisms of protein biosynthesis. When the Iron Curtain was lifted he got an opportunity to go abroad, and worked in the United States for three years from 1990-1993 (Washington University, St. Louis and UC Davis) where he continued the study of RNA processing in bacteria. In 1993 he moved to Europe and began to work at Ecole Normale Supérieure, Paris, France, where he studied the efficiency of translation initiation. At that point he began to think of applying his experimental experience from the study of prokaryotic translation to more complicated, fast developing areas of eukaryotic gene expression. Thus, since 1994, he pursued his research interests in the field of pre-mRNA splicing. In 1997, Dr, Makarov had a rare opportunity to join one of the biggest laboratories in the RNA processing field, the laboratory of Reinhard Lührmann in Germany, where pioneering work was being done in the isolation of  the small nuclear ribonucleoprotein particles. His work continued in Lührmann’s laboratory until 2005, and the emphasis of his research was on the purification and characterisation of the spliceosomes. In 2007, Dr. Makarov was appointed as a lecturer at the Division of Biosciences, Brunel University, West London, where his current research is focused around the disease-associated alternative splicing.

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October 2009: to Jason D. Lieb, PhD, University of North Carolina, Chapel Hill NC; Interactions between genes and lamin A/progerin: a window to understanding Progeria pathology and treatment

Hutchinson–Gilford Progeria Syndrome (HGPS) is caused by a mutation in the lamin A gene, resulting in production of a shortened protein called progerin. Lamin A normally plays an important function in maintaining the organization of the cell nucleus, and the mutation that creates progerin may result in a disorganization that leads to changes in gene regulation, and ultimately HGPS. However, it is not known which genes interact with lamin A in normal cells, or with progerin in the cells of HGPS patients. We hypothesize that abnormal binding or dissociation of genes with lamin A or progerin in HGPS cells causes misregulation of genes, ultimately leading to HGPS. To find which genes interact with normal lamin A and progerin across the entire genome, Dr. Lieb will perform a technique called ChIP-seq. First, he aims to identify genes that abnormally bind to or detach from lamin A or progerin in HGPS cells. Second, he will perform ChIP-seq in HGPS cells treated with a farnesyltransferase inhibitor (FTI), which shows partial efficacy in treating HGPS symptoms in mouse models. This experiment will reveal which genes’ interactions remain abnormal even after FTI treatment. The data will allow his team to predict signaling pathways that may be responsible for HGPS and the persistent HGPS symptoms reported in FTI-treated mouse models, and will provide a clue for new drugs and treatments for HGPS patients.

Dr. Lieb is an Associate Professor in the Department of Biology and Carolina Center for Genome Sciences. The projects in his laboratory are united by the scientific goal of understanding relationships between DNA packaging, transcription factor targeting, and gene expression. They use three biological systems: S. cerevisiae (baker's yeast) to address basic molecular mechanisms; C. elegans to test the importance of those mechanisms in a simple multicellular organism; and (3) cell lines and clinical samples to directly interrogate chromatin function in human development and disease. The experiments will be carried out by postdoctoral fellow Dr. Kohta Ikegami, who was trained as a graduate student at the University of Tokyo.

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October 2009: To Tom Misteli, PhD, National Cancer Institute, NIH, Bethesda, MD;  Identification of small molecule modulators of LMNA splicing

Dr. Misteli and his team are developing novel therapeutic strategies for Progeria. His group’s work focuses on interfering with the production of the progerin protein using highly specific molecular tools and to find novel small molecules to counteract the detrimental effects of progerin in patient cells. These efforts will lead to a detailed cell biological understanding of Progeria cells and bring us closer to a molecularly based therapy for Progeria.

Dr. Misteli is a Senior Investigator at the National Cancer Institute where he heads the Cell Biology of Genomes Group and the NCI Cellular Screening Initiative. He is a member of the NCI Center for Excellence in Chromosome Biology. Dr. Misteli has pioneered technology to analyze the function of genes in living cells and his work has provided fundamental insights into genome function. Dr. Misteli has received numerous national and international awards for his work and he serves in numerous advisory and editorial functions.

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August 2009: to William L. Stanford, PhD, University of Toronto, Canada
Induced-Pluripotent Stem Cells (iPSC) from HGPS patient fibroblasts to elucidate the molecular mechanism associated with diminishing vascular function


iPS cells, or Induced pluripotent stem cells are cells that started out as a mature cell type easily obtained and grown in the laboratory, and are treated with biochemical “cues” that signal the cells’ genetic machinery to turn them into immature stem cells. These stem cells are then given additional biochemical “cues” to mature once again, but not into their original cell type. For example, a skin cell (mature) can be first turned into a stem cell (immature) and then turned into a vascular cell (mature). This cutting edge technology is intensely important for Progeria research, where we cannot obtain live human blood vessel, heart and bone cells of children with Progeria for study. The ability to take a Progeria skin cell, grown easily at the PRF Cell and Tissue Bank, and create a Progeria blood vessel cell, will allow us to study heart disease in Progeria in brand new ways.

These cells will be valuable for the purpose of banking and distribution to members of the Progeria research community for basic studies and drug development. Dr. Stanford will develop multiple Progeria iPS cells to model Progeria vascular disease stem cells (VSMC), which are seriously depleted in Progeria.

Dr. Stanford is a Canada Research Chair in Stem Cell Bioengineering & Functional Genomics, and Associate Professor & Associate Director of the Institute of Biomaterials & Biomedical Engineering at the University of Toronto. He is also the co-Scientific Director of the Ontario Human iPS Cell Facility. His laboratory is focused on basic and applied research in stem cell biology, tissue engineering and modeling human disease using mouse mutagenesis and patient-specific iPS cells.

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July 2009: to Jakub Tolar, University of Minnesota, Minneapolis, MN
Correction of human progeria induced pluripotent cells by homologous recombination


Dr. Tolar’s lab has shown that allogeneic cellular therapy with mesenchymal stem cells can prolong survival in the Progeria mouse model, suggesting that cellular therapy can be of benefit to children with Progeria. However, the children have abnormal DNA repair and as such are expected to experience significant toxicities with the chemoradiotherapy needed for engraftment of cells from unrelated donors. Therefore, Dr. Tolar will limit such toxicity by developing genetically corrected cells from the Progeria children themselves, combining the novel concept of iPS cells from Progeria patients with the emerging technology for gene correction mediated by zinc finger nucleases. In this manner he aims to establish a platform for clinical translation of safer stem cell gene therapy with progeny cell types of iPS cells as a definitive treatment for children with Progeria.

Dr. Tolar is an Assistant Professor and attending physician at the University of Minnesota in the Divisions of Pediatric Hematology-Oncology and Pediatric Blood and Marrow Transplantation. Dr. Tolar's research focuses on the use of bone marrow-derived stem cells and gene therapy for correction of genetic diseases and improving outcome of blood and marrow transplantation.

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September 2008 (start date January 2009): To Kris Noel Dahl, PhD, Carnegie Mellon University, Pittsburgh, PA
“Quantification of progerin recruitment to membranes”

Hutchinson-Gilford Progeria Syndrome (HGPS) arises from an abnormal association of a mutant form of a structural nuclear lamin protein, progerin with the nuclear membrane. However, the nature of this increased association has not been determined. In this project, Dr. Dahl and her collaborators will quantify the differences in membrane association of normal lamin A and progerin using purified proteins and purified membranes. With this system, they can precisely quantify the strength of the protein-membrane interaction, determine physical changes that the membrane undergoes in contact with the protein and examine protein orientation at the interface. Also, this purified system will allow them to manipulate different variables such as membrane composition and solution charge. Some of the hypotheses to be examined are the role of the lipid tail and the charge cluster retained on progerin versus the native lamin A and the effects on membrane interaction.

Prof. Kris Noel Dahl is an Assistant Professor in the Departments of Chemical Engineering and Biomedical Engineering at Carnegie Mellon University. She obtained her PhD in Chemical Engineering at the University of Pennsylvania and did a Postdoctoral Fellowship in the Department of Cell Biology at Johns Hopkins Medical School. Dr. Dahl's group focuses on the mechanical properties of the nucleus from the molecular to the multicellular level. HGPS is one of several disease types in which mutations and molecular reorganization leads to unique nuclear mechanical properties.

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January 2008: To Bryce M. Paschal, PhD, University of Virginia School of Medicine, Charlottesville, VA
Nuclear Transport in Hutchinson-Guilford Progeria Syndrome

As a principle component of the nuclear lamina, lamin A contributes structural plasticity to the nuclear envelope membrane, provides attachment sites for chromatin, and organizes nuclear pore complexes in the membrane. Given this arrangement, we are exploring how defects in the nuclear lamina observed in Hutchinson-Guilford Progeria Syndrome (HGPS) affect the structure and function of the nuclear pore complex. These studies are designed to provide insight into how changes in nuclear architecture contribute to changes in gene expression in HGPS through transport-based mechanisms.

Dr. Paschal is Associate Professor of Biochemistry and Molecular Genetics at the University of Virginia School of Medicine where he is a member of the Center for Cell Signaling and the UVA Cancer Center. Dr. Paschal has a longstanding interest in the pathways responsible for intracellular transport.

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October 2007: To Michael A. Gimbrone, Jr., M.D., in collaboration with Guillermo Garcia-Cardena, Ph.D. and Belinda Yap, Ph.D., Center for Excellence in Vascular Biology, Brigham and Women’s Hospital, Boston, MA

“Endothelial Dysfunction and the Pathobiology of Accelerated Atherosclerosis in Hutchinson-Gilford Progeria Syndrome”

Hutchinson-Gilford Progeria Syndrome (HGPS) affects multiple organ systems in various ways, but perhaps its most serious manifestations are in the cardiovascular system, where it results in an unusually severe and accelerated form of atherosclerosis, leading to fatal heart attacks or strokes at an early age. The heart and blood vessels are lined by a transparent, single-cell-thick membrane, consisting of vascular endothelial cells (ECs), which normally forms Nature’s container for blood; pathologic changes in this vital lining, collectively termed “endothelial dysfunction”, are now recognized as critical to the development of vascular diseases, such as atherosclerosis. The purpose of our proposed studies is to determine how the mutant protein progerin, which accumulates in the nuclei of cells in HGPS, influences the structure and function of ECs, potentially leading to endothelial dysfunction. To explore this question, we have created an in vitro model system, in which the mutant protein progerin is expressed in cultured human ECs, and have begun to explore the pathologic consequences, utilizing a combination of high-throughput genomic analyses, and molecular structure-function studies. Our preliminary data indicate that progerin accumulation in human ECs leads to marked changes in their nuclear structure, and, importantly, various molecular manifestations of endothelial dysfunction. The latter include the expression of leukocyte adhesion molecules and soluble mediators that have been shown to be associated with the development of atherosclerosis. Our studies promise to provide mechanistic insights into the vascular pathologies of HGPS, and hopefully will lead to novel strategies for its effective treatment.

Dr. Gimbrone is a Professor of Pathology at Harvard Medical School (HMS) and Chairman of Pathology at the Brigham and Women’s Hospital (BWH). He also is Director of the BWH Center for Excellence in Vascular Biology. He is an elected member of the National Academy of Sciences (USA), the Institute of Medicine, and the American Academy of Arts and Sciences. His laboratory is devoted to the study of the vascular endothelium and its role in cardiovascular diseases such as atherosclerosis. Dr. Garcia-Cardena is an Assistant Professor of Pathology, HMS, and Director of the Systems Biology Laboratory in the Center for Excellence in Vascular Biology. Dr. Yap is a postdoctoral fellow in Dr. Gimbrone’s laboratory.

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May 2007: To Thomas N. Wight, PhD, Benaroya Research Institute, Seattle, WA
The use of a mouse model of HGPS to define the influence of Lamin AD50 expression on vascular extracellular matrix production and the development of vascular disease.

The extracellular matrix (ECM) is comprised of molecules that surround cells and act as both structural support and a means for a cell to communicate with its neighbors. During the development of atherosclerosis these molecules change and drive the development of the plaque, a process that takes decades in most humans. In Hutchinson Gilford Progeria Syndrome (HGPS) this process is drastically accelerated and the specific changes in ECM are not fully understood. We therefore propose to study the effect that the HGPS gene has on changes in a group of ECM molecules, called proteoglycans, which are known to play a significant role in atherosclerotic plaque development. To do this we will study a mouse model of HGPS developed in the laboratory of Dr. Francis Collins at the NIH, which develops vascular disease. Our previous investigations using this mouse have shown accumulation of a proteoglycan-rich ECM in diseased regions of the major arteries. In addition to studying proteoglycans in the vessels of these mice fed a high fat diet, we will also take cells from the vessels to grow in petri dishes, which will allow us to more closely examine the specific effect of the HGPS gene on vascular smooth muscle cell ECM. Ingrid Harten, a doctoral student in the Department of Pathology at the University of Washington will be working with Dr. Wight on this project. These studies will help to identify possible ways in which the mutant form of Lamin A found in HGPS can regulate the expression of proteoglycans in ways that lead to the development of accelerated atherosclerosis in children with HGPS.

Dr. Wight is a Research Member at the Benaroya Research Institute at Virginia Mason and an Affiliate Professor of Pathology at the University of Washington, where he was a professor from 1988 to 2000. He received his PhD from the University of New Hampshire in 1972. He is a past awardee of an American Heart Established Investigatorship, has served on NIH and AHA study sections, and currently is on the editorial board of four scientific journals. Dr. Wight's research program focuses on the cell biology and pathology of connective tissue. Specific interests include cell-extracellular matrix interactions with emphasis on the role of proteoglycans and associated molecules in the regulation of cell behavior, particularly in relation to cardiovascular disease.

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March 2007: To Jemima Barrowman, PhD, Johns Hopkins School of Medicine, Baltimore, MD; Fundamental Mechanism of Lamin A Processing: Relevance to the Aging Disorder HGPS

HGPS is caused by a mutation in the gene encoding lamin A. Normally, lamin A undergoes a transient series of biochemical modifications to its C-terminus, including the addition of a lipid (farnesyl) and a carboxyl methyl group. Ultimately, the modified C-terminal tail is cleaved off to generate the final form of lamin A. The mutation which causes HGPS prevents cleavage of the tail, resulting in a permanently farnesylated and methylated form of lamin A called progerin. A number of studies suggest that blocking the addition of the farnesyl lipid to lamin A by a drug (farnesyl transferase inhibitor; FTI) may provide a therapeutic strategy for progeria. In this proposal, we will investigate the possibility that the permanent retention of the carboxyl methyl group may also contribute to progerin’s toxic cellular effects. If so, drugs that inhibit carboxyl methyaltion could also be considered as a potential therapeutic option for progeria. We will also investigate the possibility that progerin may mimic lamin B, a permanently farnesylated relative of lamin A, thereby competing for lamin B binding partners at the nuclear membrane.

Dr. Barrowman is a Postdoctoral Researcher in the Department of Cell Biology at The Johns Hopkins School of Medicine working in the laboratory of Dr. Michaelis. Dr. Michaelis is a Professor in the Department of Cell Biology at Johns Hopkins School of Medicine with a long-term interest in the cellular machinery that modifies farnesylated proteins. Her lab has made important contributions in documenting the potential benefits of using farnesyl transferase inhibitors (FTI’s) to inhibit progerin’s toxic cellular effects.

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August 2006: To Zhongjun Zhou, PhD, University of Hong Kong, China
Stem cell therapy of Laminopathy-based Premature Aging

Stem cells are the cells that can self-renew and differentiate into a variety of different cell types. They are important because they replace the worn-out cells in the body and maintain the functional integrity of our body. The various tissues in our bodies are rapidly renewed by stem cells and it is common that stem cells decline in aged people. We hypothesize that potential of stem cells in HGPS patients are compromised and cannot provide enough new cells for the renewal of various tissues, therefore leading to accelerated ageing processes. In this project, Dr. Zhou will use a mouse model for HGPS to test if the number and the functions of stem cells in HGPS mice are declined and whether stem cells (bone marrow) derived from healthy mice will rescue the ageing phenotypes in HGPS mice. He will also investigate how the stem cells are affected in HGPS. This work directly tests the feasibility of a potential therapeutic strategy for laminopathy-based premature aging.

Dr. Zhou is an Associate Professor in the Department of Biochemistry and Faculty of Medicine at the University of Hong Kong and obtained his PhD in Medical Biochemistry from Karolinska Institute, where he also performed his postdoc training in the Institute’s Department of Medical Biochemistry and Biophysics. HI group’s main focus of research is on molecular mechanism of laminopathy-based premature ageing. In collaboration with groups in Spain and Sweden, they have made a Zmpste24 deficient mouse to serve as a mouse model for HGPS. They found that unprocessed prelamin A and truncated prelamin A found in HGPS compromise the recruitment of checkpoint response/repair proteins to damaged DNA, therefore leading to defective DNA repair which in turn contributes to accelerated ageing. Currently, they are investigating if stem cells are affected in HGPS and testing in mice if bone marrow transplantation could rescue, at least partially, the premature ageing phenotypes.

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August 2006: To Michael Sinensky, PhD, East Tennessee State University, Johnson City, TN Effect of FTIs’ on the Structure and Activity of Progerin

Hutchinson-Gilford Progeria Syndrome (HGPS) arises from a novel mutation in the gene encoding the protein prelamin A. Normally, prelamin A undergoes a series of biochemical alterations which allow it to form a part of a structure in the nucleus called the nuclear lamina. The mutant prelamin A formed in HGPS (called progerin) is defective in the last of these biochemical alterations leading to accumulation of an intermediate molecule bearing a lipid group referred to as farnesyl . Compounds, called FTIs, which block the formation of this lipid bearing version of progerin have been postulated to be of therapeutic use in the treatment of HGPS. In this proposal we describe tests of the hypothesis that progerin exhibits novelties in its molecular structure that are secondary to adding farnesyl, particularly addition of phosphate. This hypothesis will be tested as will the effects of FTIs on these postulated additions of phosphate

Dr. Sinensky is Professor and Chair in the Department of Biochemistry and Molecular Biology at East Tennessee State University’s Quillen College of Medicine. Between 1987 and 1994 his laboratory, then located at the University of Colorado Health Sciences Center, demonstrated that farnesylation of prelamin A occurred and was the first step in a proteolytic maturation pathway for the molecule. This work grew out of efforts to understand the mechanism of regulation of cholesterol biosynthesis which has also been a significant part of our research program. Since relocating in 1995 to TN, his main research interests have been in the in vitro reconstruction of the prelamin A processing pathway.

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June 2006: To Jan Lammerding, PhD, Brigham and Women's Hospital, Cambridge, MA
The role of nuclear mechanics and mechanotransduction in Hutchinson-Gilford Progeria syndrome and the effect of farnesyltransferase inhibitor treatment


Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by mutations in the gene encoding lamin A/C. Dr. Lammerding recently demonstrated that cells lacking lamin A/C are mechanically more fragile and have increased cell death and decreased protective cellular signaling in response to mechanical stimulation. Abnormal mechanical sensitivity in response to blood flow and vessel expansion could render blood vessels more susceptible to atherosclerosis, the leading cause of death in HGPS. Furthermore, increased sensitivity to mechanical stress could also contribute to bone and muscle abnormalities seen in HGPS patients. In this project, Dr. Lammerding will conduct a series of experiments to evaluate if cells from Hutchinson-Gilford Progeria syndrome patients are more susceptible to damage through mechanical stimulation. In addition, Dr. Lammerding.s experiments will test if treatment with farnesyl-transferase inhibitors (FTI), a promising new drug for HGPS, can reverse the mechanical deficiencies in HGPS cells and thus lead to a reversal of some of the tissue-specific disease phenotypes.

Dr. Lammerding is an Instructor at Harvard Medical School serving in the Department of Medicine at Brigham and Women's Hospital. His areas of interest include subcellular biomechanics and the cellular signaling response to mechanical stimulation. In particular, he is focusing on how mutations in nuclear envelope proteins such as lamin can render cells more sensitive to mechanical stress and affect their mechanotransduction signaling. Insights gained from this work can lead to a better understanding of the molecular mechanism underlying laminopathies, a diverse group of diseases including Emery-Dreifuss muscular dystrophy, HGPS, and familial partial lipodystrophy.

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June 2006: To Tom Misteli, PhD, National Cancer Institute, NIH, Bethesda, MD
Molecular Therapy Approaches for HGPS via correction of pre-mRNA Splicing

Dr. Misteli and his team are developing novel therapeutic strategies for progeria. His group’s work focuses on interfering with the production of the progerin protein using highly specific molecular tools and to find novel small molecules to counteract the detrimental effects of the progerin protein in patient cells. These efforts will lead to a detailed cell biological understanding of progeria cells and bring us closer to a molecularly based therapy for progeria.

Dr. Misteli is a Senior Investigator at the National Cancer Institute where he heads the Cell Biology of Genomes Group. He is a member of the NCI Center for Excellence in Chromosome Biology. Dr. Misteli has pioneered technology to analyze the function of genes in living cells and his work has provided fundamental insights into genome function. Dr. Misteli has received numerous national and international awards for his work and he serves in numerous advisory and editorial functions.

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June 2005: To Lucio Comai, PhD, University of Southern California, Los Angeles, CA Functional Analysis of Hutchinson-Gilford Progeria Syndrome

Dr. Comai hypothesizes that expression of the mutant Lamin A protein progerin (that causes Progeria) results in premature aging and cardiac disease as a consequence of altered composition and function of Lamin A-containing complexes within the nucleus. To test this hypothesis, he will seek to identify cellular factors that differentially interact with lamin A and progerin. These studies will provide critical information on the molecular defects of Progeria, as we work toward developing treatments at the cellular level.

Dr. Comai is Associate Professor of Molecular Microbiology & Immunology at the USC Keck School of Medicine, and a member of the Keck School’s Institute for Genetic Medicine, Norris Comprehensive Cancer Center and Research Center for Liver Diseases.

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June 2005: To Loren G. Fong, PhD, University of California, Los Angeles, CA; New Mouse Models to Study the Cause of Hutchinson-Gilford Progeria Syndrome

Since the discovery of the Progeria gene mutation more than 2 years ago, efforts have gone on in several laboratories to create a mouse that produces the "bad” lamin A (progerin) made in Progeria. Dr. Fong and his colleagues have succeeded in doing this, and now will investigate the effects of mouse progerin on the growth and metabolic properties of cells, the development of atherosclerosis, bone abnormalities and lipodystrophy in the whole animal, and finally to test whether any abnormalities can be reversed by farnesyl transferase inhibitors, at present the leading candidates for treatment of Progeria.

Dr. Fong is an Assistant Adjunct Professor at UCLA, and has joined forces with Dr. Stephen Young, a May 2005 PRF grantee, to tackle this important scientific and medical problem.

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January 2005: To Dr. Karima Djabali, PhD, Columbia University, New York, NY; Defining progerin dominant negative effects on the nuclear functions in HGPS cells

 

Dr. Djabali will conduct a fascinating series of experiments aimed at demonstrating the direct relationship of the genetic defect in Hutchinson Gilford Progeria Syndrome to numerous important binding partners in order to characterize the biological basis of disease in Progeria. This work will provide the basic data needed to lead to potential treatments.

Dr. Djabali is Assistant Professor at the Department of Dermatology at the Columbia University Medical School. She has been involved in molecular genetic studies of genetic related disease, and the fields of molecular biology, cell biology, biochemistry and proteomics.

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December 2004: To Robert D. Goldman, PhD and Dale Shumaker, PhD, Northwestern University Medical School, Chicago, Illinois
The Effects of the Major Mutation on Human Lamin A's Function in DNA Replication

Drs. Goldman and Shumaker seek to determine the molecular basis by which the Progeria gene mutations alter nuclear function to cause the premature aging effects seen in children with Progeria. This will shed light on the basic mechanisms responsible for the age-related disorders in the children, information critical to determining ways to combat the progression of the disease.

Stephen Walter Ranson Professor and Chairman of Cell and Molecular Biology at Northwestern University Medical School, Dr Goldman's research has focused on the dynamics of nuclear lamins during cell cycle, examining the relationship between their structure and function. He is an NIH member of Molecular Approaches to Cell Functions and Interactions and serves on the Human Embryonic Stem Cell Advisory Board for the Juvenile Diabetes Foundation. He has worked as an instructor and director in cell and molecular biology at the Marine Biological Laboratory, Woods Hole, Massachusetts.

Dr. Shumaker is a postdoctoral fellow of Cell and Molecular Biology at Northwestern, and has worked with Dr. Goldman studying nuclear lamins since 2001.

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August 2004 (Start date January 2005): To Stephen Young, PhD, for his project entitled "Genetic Experiments in Mice to Understand Progeria".
The aim of this research project is to use mouse models to build an intellectual foundation for designing appropriate therapies for Hutchinson-Gilford Progeria Syndrome caused by the accumulation of a mutant prelamin A (frequently called "progerin") within cells. Dr.Young's laboratory will create a mouse model of Progeria and use that model to understand how the genetic change in Progeria leads to heart disease. As concluded from the BMT workshop, the study of mouse models is a critical next-step in the process to discover treatments and the cure for Progeria. Dr. Young writes, "During the past few years, we have created several animal models to explore lamin A/C biology...We are absolutely convinced that thorough analyses of these mouse models will yield insights relevant to the design of therapies for HGPS.

Dr. Young is a Senior Investigator at the J. David Gladstone Institutes, Professor of Medicine at UCSF, and Staff Cardiologist at the San Francisco General Hospital. Dr. Young will direct and oversee the performance of all the proposed studies. Dr. Young is experienced in using genetically modified mice in biomedical research. His research group has generated and examined more than 50 lines of transgenic mice and more than a 20 gene-targeted mice. In recent years, Dr. Young has studied posttranslational protein modifications, and in particular the postisoprenylation processing steps. During the past few years, his laboratory has generated knockout mice for farnesyltransferase, Zmpste24, Icmt, and Rce1, and prenylcysteine lyase.

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April 2004: To Monica Mallampalli, Ph D, and Susan Michaelis, PhD: “Structure, Location and Phenotypic Analysis of Progerin, the mutant form of prelamin A in HGPS”
This project aims to define the structure of progerin (the abnormal protein in HGPS), develop a cell culture system that allows them to study localization of progerin; and generate progerin-specific antibodies and aptamers for the analysis of function and distribution of progerin in cells and tissues of HGPS patients. Understanding progerin structure and determining how progerin gives rise to the disease state will help reveal the molecular mechanism of HGPS, facilitating rational approaches for the development of treatments.

Dr. Mallampalli is a Postdoctoral Researcher in the Department of Cell Biology at The Johns Hopkins School of Medicine with Dr. Michaelis, Professor in Cell Biology Biophysics at The Johns Hopkins School of Medicine.

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September 2003 : To Thomas W. Glover, Ph.D. for the project entitled, " Role of Lamin A Mutations in Hutchinson-Gilford Progeria Syndrome"
This project addresses the question of why mutations in lamin A lead to the Progeria phenotype. Recently, the gene responsible for HGPS was identified, and HGPS joined a group of syndromes - the laminopathies - all of which have an underlying defect in the lamin A/C gene (LMNA). Virtually all HGPS patients have the same mutation creating an abnormal splice donor site in exon 11 of the LMNA gene. The result of the mis-splicing creates a protein missing 50 amino acids near the C-terminus. The deleted region includes a protein cleavage site that normally removes 18 amino acids including a CAAX box farnesylation site. Our research efforts are now focused on examining the effects of the causative mutation in cell culture models in order to gain a better understanding of the disease and work toward the long-term goal of discovering a cure. To this end, we are examining the effect of mutant lamin A expression on a variety of cellular phenotypes including lamin A localization, cell death, cell cycle, and nuclear morphology. These experiments involve the expression of mutant and normal lamin A from mammalian expression constructs in a variety of cell types, and confirmation by examination of the effects of the native protein in HGPS cell lines. In addition, we are developing an in vitro model for adipogenesis in HGPS, which may provide insight into the lack of subcutaneous fat, and related phenotypes, seen in HGPS patients. Finally, we hypothesize that it may be possible to correct or improve the mutant phenotype by exposing the cells to compounds that inhibit farnesylation. We have obtained a variety of such inhibitors and we are presently examining the effects of these compounds on the HGPS cellular phenotypes.

Dr. Glover is a Professor in the Department of Human Genetics at the University of Michigan with research interests in the molecular basis of human genetic disease and chromosomal instability. He is the author of over 120 research publications and book chapters. His laboratory has worked extensively on chromosome instability at fragile sites and has identified and cloned a number of human disease genes, most recently a gene responsible for hereditary lymphedema, and collaborated in the identification of the lamin A gene responsible for Hutchinson-Gilford Progeria.

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December 2003: To Joan Lemire, PhD: “Developing a smooth muscle cell model for the study of Hutchinson-Gilford Progeria Syndrome: Is aggrecan a significant component of the phenotype?”
This project aims to understand the mechanism by which progerin leads to alterations in connective tissues, and most importantly to cardiovascular disease. Children with HGPS die from myocardial infarction, congestive heart failure, and strokes. Aggrecan is a component of connective tissue, and is dramatically elevated in fibroblasts from HGPS patients. Dr. Lemire hypothesizes that this aggrecan overexpression is not limited to fibroblasts and that the arterial smooth muscle cells will also produce aggrecan, which could contribute significantly to this narrowing of the arteries in HGPS. If proven correct, preventing or reversing the lumenal narrowing through aggrecan manipulation may delay the onset of cardiovascular symptoms.

Dr. Lemire is Assistant Professor at Tufts University and recently obtained an NIH-funded grant supporting research in the role of decorin in HGPS.

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December 2003: To W. Ted Brown, MD, PhD, FACMG: “Dominant Negative Mutation Effects of Progerin”
To find a potential treatment for HGPS, the mechanism by which the mutated form of lamin A protein, progerin, leads to the disease must be understood. Progerin appears to have a dominant negative mutation; it takes on new functions and produces negative, unwanted effects on cellular functions. Dr. Brown hypothesizes that progerin binds to a key nuclear protein, to which lamin A normally does not bind, and this abnormal binding causes detrimental effects. The project focuses on characterizing this unusual binding to help explain how the mutation leads to HGPS.

Dr. Brown is Chairman of the Department of Human Genetics and Director of the George A Jervis Clinic at the New York State Institute for Basic Research. He is a world expert on Progeria, having studied the syndrome for the past 25 years. His cell banking of a number of Progeria cell lines, and his studies contributed to the eventual identification of LMNA mutations in Progeria.

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May 2002: To Associate Professor Anthony Weiss at the University of Sydney
Title of project: Candidate Molecular Markers for Hutchinson-Gilford Progeria Syndrome

Project Description: Accurate diagnosis of Hutchinson-Gilford Progeria Syndrome (HGPS) requires a reliable marker. We have used glyean detection to describe gp200 and identified key overexpressed transcripts that are excellent candidates for HGPS markers in cultured fibroblasts. This one-year project will allow us to use proteomics to identify gp200 and real time RT-PCR methods for examining a leading transcribed candidate marker hgpg200. We will improve the sensitivity of our published gp200 assay, expand the utility of specific transcript analysis, and develop a sensitive assay to facilitate marker detection.

This work is important to children with HGPS. (1) It will aid early and accurate diagnosis. (2) This project marks the first time that this combination of proteomics and microarrays/real time RT-PCR tools is used to explore the molecular features of HGPS. (3) We will identify key molecules that distinguish HGPS. Their identification will provide us with information on the molecular biology and biochemistry of HGPS. (4) By the end of year 1, we expect to provide an assay that can be reliably considered, beyond the current grant, in small biopsy samples and buccal cells taken by gentle swabs.

Biographical Sketch: Tony Weiss is founding Chair of the Molecular Biotechnology Program University of Sydney, Associate Professor of Biochemistry in the School of Molecular and Microbial Biosciences University of Sydney, Honorary Visiting Scientist in Molecular and Clinical Genetics at Royal Prince Alfred Hospital, and Visiting Professor at the National University of Singapore. Tony was given the Roslyn Flora Goulston Prize and an Australian Postgraduate Research Award then made an ARC Postdoctoral Fellow, after which he moved to the USA as a NIH Fogarty International Fellow. He received further awards including a Fulbright Fellowship at Stanford University before returning to Australia as a CSIRO Postdoctoral Scholar to take up a Faculty position at the University of Sydney. He has twice been a Thomas and Ethel Mary Ewing Scholar and was made a Royal Society Exchange Scholar to pursue research studies in the LTK. Tony was recognized by the Australian Society for Biochemistry and Molecular Biology for distinguished contributions to the field of Biochemistry and Molecular Biology and was awarded the Amersham Pharmacia Biotechnology Medal. He also received the David Syme Research Prize and Medal which is awarded for the best original research work in Biology, Chemistry, Geology or Physics, produced in Australia, during the preceding two years.

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January 2001 (Start date July 2001): To John M. Sedivy, PhD Brown University, Providence, RI; & Junko Oshima, MD, PhD, University of Washington, Seattle, WA, Cloning of the Gene for Hutchinson-Gilford Progeria Syndrome by Somatic Cell Complementation"

John M. Sedivy is a Professor of Biology and Medicine in the Department of Molecular Biology, Cell Biology and Biochemistry at Brown University. After completing his undergraduate studies at the University of Toronto in 1978, he obtained his PhD in 1984 in Microbiology and Molecular Genetics from Harvard University. After four years of postdoctoral training in somatic cell genetics in the laboratory of the Nobel laureate Philip Sharp at the Massachusetts Institute of Technology he started his independent research career in 1988 on the faculty of Yale University. He was named Presidential Young Investigator in 1990 and received the Andrew Mellon Award in 1991.

He moved to Brown University in 1996, where he teaches genetics and supervises a research group working on basic cancer biology and mechanisms of aging of human cells and tissues. He has served and continues to serve on numerous peer review committees for the National Institutes of Health and the American Cancer Society. His laboratory has been continuously funded by the National Institutes of Health, and has maintained a productive publication record in peer reviewed journals. In 2000 John Sedivy was named Director designate of the Center for Genetics and Genomics which is currently being established at Brown University.

The goal of the research project is to identify the gene whose mutation is responsible for the Hutchinson-Gilford Progeria Syndrome (HGPS). The gene for another progeroid syndrome, Werner's syndrome, has recently been identified through genetic studies of several large afflicted families. Unfortunately, this approach cannot be used in the case of HGPS because there are no families with extended HGPS pedigrees. Dr. Sedivy and his collaborator, Dr. Frank Rothman, have instead proposed to identify the HGPS gene by genetic studies of cells obtained from HGPS patients. This approach will take advantage of two recent developments in biotechnology: first, high density cDNA or oligonucleotide microarrays (commonly known as "Gene Chips"), which allow the study of numerous genes at one time; and second, retrovirus vector systems, which make it possible to engineer highly efficient transfer of genetic information from cell to cell. The researchers will first attempt to identify gene expression patterns that differentiate HGPS cells from normal cells, and then use the retrovirus vector technology to search for the gene (or genes) in normal cells that can "cure" the HGPS cells.

Frank G. Rothman, PhD, co-investigator

Frank G. Rothman is Professor of Biology and Provost, Emeritus at Brown University. He received his Ph.D. degree in chemistry from Harvard University in 1955. From 1957-1961, after two years of service in the U.S. Army, he was a postdoctoral research fellow and associate in molecular genetics at M.I.T. From 1961 until his retirement in 1997 he was on the Biology faculty of Brown University. He taught biochemistry, genetics, and molecular biology at all levels. His research on gene expression in microorganisms was continuously funded by the National Science Foundation from 1961 to 1984. He served as Dean of Biology from 1984-1990, and university Provost from 1990-1995. In the late 1980s he carried out research on aging in the roundworm, Caenorhabditis elegans. He taught courses in the Biology of Aging in 1988 and again in 1996. As Professor Emeritus, he has engaged in collaborative studies on the biology of aging, with a focus on Progeria."

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December 2001: (Start date February 2002): To Thomas W. Glover, Ph.D.
"Genome Maintenance in Hutchinson-Gilford Progeria Syndrome"

Thomas W. Glover, Ph.D.: Dr. Glover is a Professor in the Departments of Human Genetics and Pediatrics at the University of Michigan, Ann Arbor, MI. His research focus is the molecular genetics of human genetic disorders and studies of chromosome instability and DNA repair. He has succeeded in identifying or cloning a number of human disease genes including those for Menkes syndrome, a common form of Ehlers-Danlos syndrome, and hereditary lymphedema. He has over 100 peer-reviewed scientific publications and has had continuous NIH grant support. He has served on several Editorial Boards and is a grant reviewer for the March of Dimes Birth Defects Foundation and the National Institutes of Health.

Michael W. Glynn, M.S. , co-investigator, is a senior graduate student pursuing a Ph.D. in Dr. Glover's laboratory in the Department of Human Genetics at the University of Michigan. He has completed qualifying for candidacy, and has finished all class work and teaching requirements. Honors include the James V. Neel Award for academic excellence awarded by the Department of Human Genetics. He is an author on several papers, a book chapter and two patents. Michael received a Masters of Science degree in Microbiology from the University of Connecticut. He went on to supervise the DNA Diagnostic Lab at Yale Medical School under the direction of Dr. Allen Bale.

The ultimate goal is to understand the basic defect responsible for HGPS. In this project, we will examine specific aspects of genome maintenance in HGPS cells. We will focus on three areas, telomere dynamics, spontaneous mutation rate, and specific.shtmlects of DNA repair. We will quantitatively measure rates of telomere degradation in HGPS fibroblasts by infecting cells with an hTERT (telomerase catalytic subunit) expressing retrovirus, modified to allow for strict control of telomerase expression. In addition, DNA maintenance will be examined to determine if HGPS, like many premature aging syndromes, involves a defect in DNA repair or replication. Studies will include examination of basal p53 levels in HGPS fibroblasts, the ability of HGPS fibroblasts to repair specific DNA lesions using lesion-specific antibodies, and examination of the rate of spontaneous mutations in HGPS fibroblasts. Many of the studies will include telomerase-immortalized fibroblast cell lines so that experiments can be performed without measuring effects caused by the premature senescence of HGPS fibroblasts. The proposed studies have the potential to give concrete answers as to whether the underlying defect in HGPS is due to faulty genome maintenance. Elucidation of cellular phenotypes associated with HGPS will be a valuable tool in determining the defective molecular pathways and, ultimately, in discovering the disease gene(s).

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August 1999: To Leslie B. Gordon, MD, PhD
"The Pathophysiology of Arterioscleros is in Hutchinson-Gilford Progeria Syndrome"

 

January 2000: To Leslie B. Gordon, MD, PhD
"The Role of Hyaluronic Acid in Hutchinson-Gilford Progeria Syndrome"

Dr. Leslie Beth Gordon is an Instructor in Pediatrics at Hasbro Children's Hospital in Providence, Rhode Island and a Research Associate at Tufts University School of Medicine in Boston, Massachusetts, where she conducts her research on HGPS. She completed the combined MD, PhD program at Brown University School of Medicine in 1998, where she achieved the top-ranking category of outstanding in the medical program and became a member of the Sigma Xi Honor Society. . Prior to that, she received her Masters in Science from Brown University in 1991. Her Bachelor of Arts degree from the University of New Hampshire was awarded in 1986.

Dr. Gordon is focusing on the one consistent difference between Hutchinson-Gilford Progeria Syndrome (HGPS) patients and healthy children: the HGPS patients have much higher levels of a particular compound - hyaluronic acid (HA) - in their urine. HA is necessary for life because it helps hold tissue together, but too much of it might be a bad thing. HA concentrations creep up in elderly people, and plaques that build up in the blood vessels of people who die of heart disease are steeped in HA. The children with HGPS have these same plaques throughout their bodies, and that's what plays a major role in causing heart attacks and strokes. The idea that HA contributes to heart disease is not new, but work in this area has been fostered recently by new analytical tools. In this relatively unexplored area of research, Dr. Gordon is trying to follow the trickle of evidence to its source to find out whether the disease grows more severe as HA levels rise and to establish whether the chemical does indeed promote plaque formation. If such a connection were confirmed, it could lead to therapies that fight both Hutchinson-Gilford Progeria Syndrome and cardiovascular disease by lowering HA levels. "Any treatments that help these children will very likely help millions of people with cardiovascular disease and potentially other problems associated with aging", says Dr. Gordon.

Dr. Gordon is working in the laboratory of Dr. Bryan P. Toole, Professor of Anatomy at Tufts University School of Medicine. Others assisting in the project are Ingrid Harten M.S., Margaret Conrad, R.N., and Charlene Draleau, R.N

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