The studies proposed in Project 2 aim to identify mechanisms leading to accelerated initiation of atherosclerotic lesions in diabetes. We will focus on endothelial cells and macrophages - the two most important cell types in lesion initiation. The experiments will be carried out in isolated mouse endothelial cells and macrophages, and in a transgenic LDL receptor-deficient mouse model in which type 1 diabetes can be induced by a virus (the LDLR-/-;GP mouse). Based on preliminary experiments, we hypothesize that the atherogenic and inflammatory effects of diabetes are dependent on formation of fatty acyl-CoAs. We propose to directly test the contribution acyl-CoA synthesis in the effects of diabetes on lesion initiation by targeted modulation of expression levels of one of the principal enzymes involved in acyl-CoA synthesis in endothelial cells and macrophages (long-chain acyl-CoA synthetase 1;AcsM). The goal of Project 2 is to address the following three questions: 1) Does acyl-CoA synthesis regulate inflammatory processes in macrophages and endothelial cells?;2) Does increased acyl-CoA synthesis in macrophages mimic the effects of diabetes on inflammatory mediators and lesion initiation in LDLR-/-;GP mice?;3) Does inhibition of acyl-CoA synthesis in endothelial cells or macrophages retard lesion initiation in our mouse model of accelerated diabetic atherosclerosis? These studies will increase our understanding of the molecular mechanisms involved in diabetes-accelerated lesion initiation. Identification of such mechanisms might be used to develop drugs to target cardiovascular complications of type 1 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL092969-50
Application #
8105144
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
50
Fiscal Year
2010
Total Cost
$407,598
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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