Mechanistic studies of a PPAR-g mutation that causes lipodystrophy &diabetes

Summary

Principal Investigator: OLGA IGOR ASTAPOVA
Abstract: Although insulin resistance is a key component of type II diabetes, the molecular mechanisms controlling insulin sensitivity have not been fully elucidated. Understanding the etiology of insulin resistance will therefore be of tremendous importance for developing better screening, treatment and prevention targets to combat the rising threat of metabolic disorders. Peroxisome proliferator-activated receptor gamma (PPARg) has been implicated in the insulin signaling pathway as the target of thiazolidinediones, drugs that have recently been employed in the management of insulin-resistant disorders for their insulin-sensitizing effects. PPARg is a ligand-activated nuclear receptor with a well-characterized structure that binds PPAR response elements and regulates transcription of target genes by recruiting coactivators and/or corepressors. Although many PPARg-regulated genes have been identified, the exact set of PPARg target genes that mediate improvements in insulin sensitivity in vivo is largely unknown. The goal of this project is to shed light on this issue by studying a unique, recently discovered PPARg mutation that causes familial partial lipodystrophy (FPLD), an extreme form of type II diabetes. This project will take advantage of the particular properties of this mutation, which makes a conservative single change (E157D) in the DNA binding domain of the receptor. Our preliminary data show that this mutation alters the DNA sequence recognition specificity of the receptor, resulting in a distinctly different pattern of transcription of several known PPARg target genes. These findings led to the hypothesis that forms the basis for this proposal: the E157D PPARg causes diabetes through misregulation of key metabolic genes. There are two specific aims: 1) Characterize the effects of the E157D mutation on DNA binding and transcriptional activation of a set of known PPARg target genes, and 2) Identify the global set of genes that are misregulated by E157D PPARg. Standard in vitro techniques for DNA binding and transcriptional activity will be used to compare mutant and wild type PPARg function. Human cell lines expressing wild-type and mutant PPARg will be generated, and microarray analysis of gene expression as well as chromatin immunoprecipitation analysis of selected genes will be used to identify genes misregulated by E157D PPARg. RELEVANCE. Results from this study will identify genes or sets of genes that were not previously recognized as being involved in the etiology of metabolic diseases such as lipodystrophy and in particular diabetes. This knowledge may advance possibilities for screening, treatment and prevention of diabetes and other metabolic diseases.
Funding Period: 2009-09-08 - 2014-08-07
more information: NIH RePORT

Top Publications

  1. pmc Clinical and molecular characterization of a severe form of partial lipodystrophy expanding the phenotype of PPARγ deficiency
    Philippe M Campeau
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
    J Lipid Res 53:1968-78. 2012

Detail Information

Publications1

  1. pmc Clinical and molecular characterization of a severe form of partial lipodystrophy expanding the phenotype of PPARγ deficiency
    Philippe M Campeau
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
    J Lipid Res 53:1968-78. 2012
    ..Together, our results support the role of PPARγ in controlling homeostasis of multiple systems beyond lipid metabolism...

Research Grants62

  1. A novel axis regulates adipocyte plasticity
    Sean Hartig; Fiscal Year: 2013
    ..I anticipate that my studies will provide new clues into the complex regulatory networks controlling energy balance in fat cells. If my hypothesis is true, the Ubc9/miR-30a axis might be exploited in novel therapies to manage T2DM. ..
  2. NUCLEAR HORMONE RECEPTORS IN ADIPOCYTE DIFFERENTIATION
    Mitchell A Lazar; Fiscal Year: 2013
    ..Our innovative approach will elucidate mechanisms underlying target gene- and tissue-specificity of PPAR?, which can be translated to the design of more selective insulin sensitizers to combat the epidemic of metabolic disorders. ..
  3. Metabolic Signals Regulating GLUT4 Expression in vivo
    Ann Louise Olson; Fiscal Year: 2013
    ..Completion of the aims of this proposal will help us to understand more about the GLUT4 promoter and more about the intracellular signaling during insulin- deficiency and insulin-resistance. ..
  4. The Role of Myc in ChREBP-dependent, Glucose-stimulated Gene Expression
    Donald K Scott; Fiscal Year: 2013
    ....
  5. Circadian Repressors Cry1 and Cry2 Modulate Nuclear Hormone Receptor Function
    Katja A Lamia; Fiscal Year: 2013
    ..This project involves the study of a novel regulator for nuclear hormone receptor function and will contribute to the knowledge base needed for the development of therapeutic strategies to treat metabolic disease. ..
  6. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  7. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  8. Role of FoxO1 in Lipid Metabolism
    REBECCA ANNE HAEUSLER; Fiscal Year: 2013
    ..These data will provide a roadmap to design new therapeutic interventions in the treatment of dyslipidemia within the rapidly growing population of people with the metabolic syndrome. ..
  9. High-Content Screening for Peroxisome Biogenesis for Type-II Diabetes.
    JONATHAN ZACHARY SEXTON; Fiscal Year: 2013
    ..We have validated a known therapeutic compound in mice as a potent activator in our assay to use for compound screening and secondary/orthogonal assay development. ..
  10. Novel Methods to Assess the Effects of Chemicals on Child Development
    Susan L Schantz; Fiscal Year: 2013
    ..This Center's research will fill an important gap in our knowledge by investigating the effects of these chemicals, both alone and combination with a high fat diet on reproductive and neural development. ..
  11. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013
    ..abstract_text> ..
  12. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  13. Vanderbilt Diabetes Research Center
    Alvin C Powers; Fiscal Year: 2013
    ..Because of the VDRTC and the environment it creates, VDRTC-affiliated investigators have made important scientific contributions related to diabetes, obesity, and metabolism. ..
  14. An integrative approach to construct a regulatory network effected by TDZs
    Kyoung Jae Won; Fiscal Year: 2013
    ....
  15. Basic and Clinical Studies of Cystic Fibrosis
    Raymond A Frizzell; Fiscal Year: 2013
    ..The Core Center will operate a Pilot and Feasibility Program to bring new investigators into CF research. This Center emphasizes the translation of basic knowledge into applied therapeutics. ..
  16. Notch and Regulators of Notch Signaling Impact Both Glucose and Lipid Metabolism
    UTPAL BHAGIRATH PAJVANI; Fiscal Year: 2013
    ..Pajvani will need in order to become an independent translational medical researcher and a productive member of the academic medical community. ..
  17. Novel Subunit of NF-kB Confers Gene Regulatory Specificity
    Fengyi Wan; Fiscal Year: 2013
    ..These results will also provide potential novel therapeutic targets for the treatment of cancer and inflammatory disease, and may have implication for NF-kB-related diseases in general. ..
  18. Role of TWEAK in Skeletal Muscle Metabolism
    Ashok Kumar; Fiscal Year: 2013
    ..Successful completion of this project will provide critical insights about sarcopenia durin aging and type II diabetes and provide novel avenues for therapeutic interventions. ..
  19. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
    ..The long-term objective of this PPG is to advance basic understanding of vector-cell-animal model interactions for safe gene delivery. ..
  20. Pax6 as a key regulator of lens development
    Ales Cvekl; Fiscal Year: 2013
    ..abstract_text> ..
  21. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  22. Mechanisms of Dietary Lipid Induced Insulin Resistance
    Peter D Reaven; Fiscal Year: 2013
    ..abstract_text> ..
  23. Epigenetics of Obesity and Insulin Resistance
    Jane Kim; Fiscal Year: 2013
    ..Jerrold Olefsky. This approach is designed to draw on my strengths as a bench scientist and pediatric endocrinologist, providing an independent focus of research and platform for future R01 funding. ..
  24. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  25. Exercise Dose-Response Effects in Prediabetes: Responses and Mechanisms
    William E Kraus; Fiscal Year: 2013
    ....
  26. The Role of H6PDH and 11beta-HSD1 in Type 2 Diabetes and Obesity
    Yanjun Liu; Fiscal Year: 2013
    ..Blocking the effects of H6PDH on 112-HSD1 may represent a new strategy in the effective treatment of type 2 diabetes and obesity through reduction of tissue GC availability mediating insulin sensitivity and glucose homeostasis. ..
  27. Novel Mechanistic Targets of Steroid Hormones in the Brain
    Meharvan Singh; Fiscal Year: 2013
    ....
  28. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  29. Function and specificity of thiazolinedione induced eRNAs
    Jill M Marinis; Fiscal Year: 2013
    ..Identification of novel adipocyte specific factors and understanding their mechanism of action has the potential of tailoring therapeutics for cell specific actions to minimize adverse side-effects of TZDs. ..
  30. Role of Eicosanoids in Renal Function
    NANCY JOAN BROWN; Fiscal Year: 2013
    ..These are needed for the development of meaningful approaches for: a) the unequivocal definition of human pathophysiological significance, and b) future pharmacological targeting, and clinical diagnosis and intervention. ..
  31. Hepatic Lipid Mobilization by Nuclear Hormone Receptors
    Yoon Kwang Lee; Fiscal Year: 2013
    ....
  32. Identification of Prediabetes Genes by Expression Linkage Analysis
    Christopher P Jenkinson; Fiscal Year: 2013
    ..abstract_text> ..
  33. OBESITY, ADIPOGENESIS, AND LIPID LIGANDS
    Clay F Semenkovich; Fiscal Year: 2013
    ..Identifying novel pathways for altering the function of fat cells has the potential to improve the metabolic milieu of obesity and treat obesity-associated diseases. ..
  34. Function of Toll-Like Receptors Throughout Gestation
    GIL G MOR; Fiscal Year: 2013
    ....
  35. Role of NCoR in Adipose Tissue
    Maryam Ahmadian; Fiscal Year: 2013
    ..abstract_text> ..
  36. Dynamics of Altered Metabolic States using a Microfluidic Living Cell Platform
    Abhinav Bhushan; Fiscal Year: 2013
    ..The advisory team has a very strong collaborative record of accomplishment and set of prior accomplishments that will make this partnership function seamlessly and successfully. ..
  37. Molecular and Cellular Basis for Digestive Diseases
    Richard M Peek; Fiscal Year: 2013
    ..The Administrative Core also contains Biostatistics and Enrichment Programs and oversees the financial management and operation of the VDDRC. ..
  38. Circadian Clock Disruption: A Mechanism for Dioxin-induced Metabolic Syndrome
    Shelley A Tischkau; Fiscal Year: 2013
    ..This proposal examines the novel hypothesis that dioxins exert their action through aryl hydrocarbon receptor-mediated uncoupling of homeostatic regulation of organismic circadian rhythms. ..
  39. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..