Function and specificity of thiazolinedione induced eRNAs

Summary

Principal Investigator: Jill M Marinis
Abstract: DESCRIPTION (provided by applicant): The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR?) is a master regulator of adipogenesis and metabolism. The widely used anti-diabetic class of thiazolinedione (TZD) drugs target PPAR? to decrease circulating levels of glucose, insulin, triglycerides, and free fatty acids;however, te molecular mechanisms and cell targets of these actions are not completely understood. We have employed a novel genome-wide technique, Global Run-On Sequencing (GRO-seq) to identify TZD-induced long non- coding RNAs (lncRNA) from PPAR? bound enhancers, (eRNAs), in adipocytes. We hypothesize that eRNAs mediate PPAR? expression profiles in adipocytes and dictate cell-specific TZD-induced gene expression networks. The first aim of this proposal is dedicated to determining the physiological significance and mechanism of action of eRNAs in adipocytes. Both global and individual functions of eRNAs will be tested in experiments using RNAse or eRNA knockdown and overexpression. The second aim uses GRO-seq to identify eRNAs in macrophages. GRO-seq datasets of adipocytes and macrophages will be compared to identify cell type specific eRNAs. 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.
Funding Period: 2013-07-01 - 2016-06-30
more information: NIH RePORT

Detail Information

Research Grants31

  1. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
    ....
  2. Connection of Mineral and Energy Metabolism by the Nuclear Receptor PPAR-gamma
    Yihong Wan; Fiscal Year: 2013
    ..Therefore, this investigation will significantly impact the broader scientific, clinical, and patient community. ..
  3. Transcriptional role of TLE3 in brown adipose tissue development and metabolism
    Claudio J Villanueva; Fiscal Year: 2013
    ..The proposed studies are a logical transition from my postdoctoral studies in adipogenesis to the burgeoning field of brown adipocyte biology. ..
  4. 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. ..
  5. 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. ..
  6. 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. ..
  7. Prenatal Programming of Reproductive Health and Disease
    Vasantha Padmanabhan; Fiscal Year: 2013
    ..abstract_text> ..
  8. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  9. Epigenomic Profiling of Normal and Diabetic Pancreatic Beta-Cells
    Klaus H Kaestner; Fiscal Year: 2013
    ..We will determine the "epigenetic", that is not mutation based, changes in the genome of the diabetic beta-cell that cause it to fail. This work will identify new potential drug targets for the treatment of type 2 diabetes. ..
  10. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  11. 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. ..
  12. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  13. Translating human PPARy binding regions to gene regulation and metabolic disease
    RAYMOND EDWARD SOCCIO; Fiscal Year: 2013
    ..Soccio from the mentored to the independent phase of this 5 year career development award. These studies of the human PPAR cistrome have potentially great translational relevance to the epidemics of diabetes and obesity. . ..
  14. Role of NCoR in Adipose Tissue
    Maryam Ahmadian; Fiscal Year: 2013
    ..abstract_text> ..
  15. 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. ..
  16. 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. ..
  17. An investigation of the mechanisms by which down-regulation of lipoprotein lipase
    Jheem D Medh; Fiscal Year: 2013
    ..This project will clearly establish the regulatory relationship between LPL expression and insulin sensitivity, and will facilitate the development of novel approaches to manage insulin resistance in diabetes. ..
  18. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013
    ..abstract_text> ..