A new PPG application is proposed to identify and characterize gene networks in adipocytes and macrophages that influence insulin action. A combination of molecular, cellular, genetic and bioinformatics approaches will be used to define the components and behaviors of these networks at a genome-wide scale. The proposed studies will test the hypothesis that macrophage/adipocyte interactions result in altered programs of inflammatory gene expression in both cell types that contribute to insulin resistance. We will further test the hypothesis that PPARy agonists exert insulin-sensitizing effects by counter-regulating feed forward mechanisms that amplify inflammation within obese adipose tissue. Microarray and genome-wide location analysis will be performed to define the roles of NCoR/SMRT corepressor complexes as transcriptional checkpoints in PPARy-, NF-KB-, and AP-1-dependent gene expression and determine the importance of these complexes in mediating anti-inflammatory actions of PPARy agonists. Candidate genes identified by microarray studies and associated bioinformatics approaches will be tested for their pathophysiological roles in high fat diet-induced insulin resistance in mouse models. The results of these studies are likely to lead to new insights into the mechanisms underlying obesity-associated insulin resistance that can be exploited for development of novel therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK074868-04
Application #
7807958
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (J1))
Program Officer
Margolis, Ronald N
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$1,498,959
Indirect Cost
Name
University of California San Diego
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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