PPAR-Gamma's Role in Aberrant Adipogenesis and Fibrosis in Systemic Sclerosis

Summary

Principal Investigator: BENJAMIN DOUGLAS KORMAN
Abstract: DESCRIPTION (provided by applicant): Systemic sclerosis (SSc) is a devastating progressive multisystem fibrotic disease which affects the skin and other organs;there are currently no approved or effective therapies. The disease affects an estimated 300,000 Americans and is a major public health concern with high morbidity and mortality. The process of fibrosis is a common final pathway for multiple human diseases and diseases involving fibrosis cause nearly 45% of all deaths in industrialized nations. In this proposal, I plan to investigate the role of adipose PPAR-gamma on the process of fibrosis and specifically in animal models of SSc. Because we have observed that skin fibrosis is associated with subcutaneous adipose tissue loss and because work in our lab has demonstrated that PPAR-gamma is important in SSc pathogenesis, I hope to discover whether adipocytes play an important role in fibrosis and how PPAR-gamma may influence this. I first plan to investigate whether adipocyte PPAR-gamma gain of function can prevent fibrosis by applying the bleomycin-induced skin fibrosis model of SSc to transgenic mice with either constitutively activated PPAR-gamma or loss of PPAR-gamma repressors. I will then perform cell culture experiments to determine how PPAR-gamma function may alter adipocyte cell fate, production of soluble factors, and adipocyte effects on other important cells including fibroblasts and macrophages. This work will help determine the relevance of fat to the process of fibrosis and could potentially be paradigm shifting by implicating adipose tissue as an important contributor to fibrogenesis in SSc. The work in this training grant will be performed under the supervision of Dr. John Varga, one of the world's leading experts in SSc and the pathogenesis of fibrosis. In addition to having the mentorship of Dr Varga, because of the multidisciplinary nature of this project, I will have consultants with expertise in adipose biology and nuclear receptors (Dr Barish) as well as in mouse pathology (Dr. Tourtellotte). While SSc is a multiorgan disease, this work focuses on dermal fibrosis and therefore is highly relevant to the NIAMS mission of supporting research into the causes of musculoskeletal and skin disease and the training of scientists to perform such research. This mentored project consists both of formal didactics and research training and will lead me to develop expertise in PPAR-gamma biology and the relationship between adipogenesis and fibrosis. This work will help me to develop the knowledge and skills necessary to become an independent investigator and ultimately a future leader in rheumatology and the field of SSc research.
Funding Period: 2013-07-01 - 2015-06-30
more information: NIH RePORT

Detail Information

Research Grants30

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  2. Oklahoma Sjogren's Syndrome Center of Research Translation
    KATHY L SIVILS; Fiscal Year: 2013
    ..This will in turn create opportunities for new diagnostics, prognostic and therapeutic strategies that will benefit patients with this and other related diseases. ..
  3. ADAPTATIONS TO HYPOXIA
    Kurt R Stenmark; Fiscal Year: 2013
    ..abstract_text> ..
  4. Maternal Obesity affects AMP-Kinase in Muscle Cell Differentiation
    Min Du; Fiscal Year: 2013
    ....
  5. Innate immunity in dermal fibrosis and systemic sclerosis
    ROBERT A LAFYATIS; Fiscal Year: 2013
    ....
  6. THE UCLA CENTER FOR IN VIVO IMAGING IN CANCER BIOLOGY
    Harvey R Herschman; Fiscal Year: 2013
    ....
  7. Role of lipid intermediates in the limited human adipose tissue expandability ass
    Angela R Subauste; Fiscal Year: 2013
    ..At the completion of these studies we will have defined the faulty lipid signal present in obese insulin-resistant individuals. ..
  8. The Wake Forest Center for Botanical Lipids and Inflammatory Disease Prevention
    Floyd H Chilton; Fiscal Year: 2013
    ....
  9. Harnessing mechanical signals to control mesenchymal stem cell fate
    JANET E RUBIN; Fiscal Year: 2013
    ....
  10. Targeting Adiponectin Signaling: Novel Peptide Therapy for Scleroderma
    John Varga; Fiscal Year: 2013
    ..The project is high impact since there are no approved treatments for scleroderma. Moreover, the results will have a strong impact on myriad fibrosing diseases that currently lack effective treatment. ..
  11. Predictive Ability of Gene Expression Signatures In Skin as SSc Biomarkers
    MONIQUE EVANGELINE HINCHCLIFF; Fiscal Year: 2013
    ....
  12. Glycan Modulation of Inflammatory Responses
    Ajit P Varki; Fiscal Year: 2013
    ..abstract_text> ..
  13. Core Center for Musculoskeletal Disorders
    Louis J Soslowsky; Fiscal Year: 2013
    ..abstract_text> ..
  14. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  15. Zimmerman Program for the Molecular and Clinical Biology of VWD
    Robert R Montgomery; Fiscal Year: 2013
    ..Taken together this PPG will set the stage for the appropriate diagnosis and phenotypic understanding of VWD - both in the US and throughout the world. ..
  16. Ether Lipids, Elcosanoids, and Lung Cell Pathophysiology
    CHRISTINA CARROLL LESLIE; Fiscal Year: 2013
    ..By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses. ..
  17. Cellular Dynamics of Subcutaneous Fat Distribution in Obese Women
    Eric Ravussin; Fiscal Year: 2013
    ....
  18. The Role Of Lysophosphatidic Acid (LPA) And Its Receptor, LPA1 In Scleroderma
    Flavia V Castelino; Fiscal Year: 2013
    ..These studies will serve as a foundation for Dr. Castelino to become an independent translational investigator. ..
  19. Center for Reproductive Science and Medicine
    Pamela L Mellon; Fiscal Year: 2013
    ..The SCCPIR Human Ovary Tissue Bank provides tissue to NIH-funded investigators nation-wide. ..
  20. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  21. 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. ..
  22. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
    ..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
  23. Autoimmunity Center of Excellence (ACE) at Stanford
    CHARLES GARRISON FATHMAN; Fiscal Year: 2013
    ..The Stanford ACE proposes clinical research projects that encompass three different autoimmune diseases (SSc, psoriatic arthritis and SJIA), and proposes to study the MoA of therapeutics for preventing or treating different Al diseases. ..
  24. DETECTION AND MODELS OF TOXICANT EXPOSURE
    Robert H Tukey; Fiscal Year: 2013
    ..Our combined efforts are anticipated to provide new insights into the molecular mechanisms that lead to environmental illness, and improve our understanding of the consequences of exposure to Superfund site contaminants. ..
  25. Cellular Senescence and Aging
    James L Kirkland; Fiscal Year: 2013
    ..Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years. ..