Premature atherosclerosis is the major cause of morbidity and mortality in both types 1 and 2 diabetes. The overall objective of this Program Project is to better understand biochemical and molecular mechanisms involved in the pathogenesis of diabetic macrovascular disease. The program project is comprised of 4 inter-related projects and 3 cores. Project 1 will study the the role of an inflammatory molecule, serum amyloid A (SAA) in mediating the interaction of atherogenic lipoproteins with the vascular wall, thereby enhancing atherosclerosis. It will investigate how SAA alters the interaction of lipoproteins with extracellular vascular matrix molecules and alters cellular lipid metabolism and endothelial activation providing insight into the link between inflammation and atherosclerosis in diabetes. Project 2 is aimed at understanding the role of fatty acyl-CoA synthesis in the initiation of atherosclerosis in diabetes. Acyl-CoA synthesis is increased in diabetes. The effect of modulation of acyl-CoA synthesis in endothelial cells and macrophages on lesion initiation and inflammation is the focus of this project. Project 3 will study the role of diabetes on the regulation of reverse cholesterol transport, a process that plays a critical role in atherogenesis. The effect of diabetes on transporters that play critical roles in removing excess lipids from cells will be studied in this project. Project 4 will study biochemical pathways involved in glycation and glycoxidation reactions that play a role in damaging HDL, thereby accelerating atherosclerosis in diabetes. This project will also assess how the diabetic milieu alters HDL's protein composition and its anti-inflammatory properties. Diabetes-mediated alterations in HDL composition and function could impair HDL's atheroprotective functions and accelerate atherosclerosis in diabetes. These projects will be supported by an administrative and 2 scientific cores: The Mouse and Tisssue Core will provide the projects with mice and histochemical and immunohistochemical evaluation of tissues from several mouse models of diabetes. The Mass Spectrometry Core will provide sophisticated biochemical support for the in vitro and in vivo studies proposed in all the projects. The increased understanding of the pathogenesis of the premature vascular disease in diabetes that will be derived has important therapeutic implications for the prevention and treatment of macrovascular disease in diabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL092969-52
Application #
8279334
Study Section
Special Emphasis Panel (ZHL1-PPG-J (M2))
Program Officer
Ershow, Abby
Project Start
1997-03-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
52
Fiscal Year
2012
Total Cost
$2,226,221
Indirect Cost
$858,119
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Krishack, Paulette A; Sontag, Timothy J; Getz, Godfrey S et al. (2016) Serum amyloid A regulates monopoiesis in hyperlipidemic Ldlr(-/-) mice. FEBS Lett 590:2650-60
Ronsein, Graziella E; Hutchins, Patrick M; Isquith, Daniel et al. (2016) Niacin Therapy Increases High-Density Lipoprotein Particles and Total Cholesterol Efflux Capacity But Not ABCA1-Specific Cholesterol Efflux in Statin-Treated Subjects. Arterioscler Thromb Vasc Biol 36:404-11
Shimizu-Albergine, Masami; Van Yserloo, Brian; Golkowski, Martin G et al. (2016) SCAP/SREBP pathway is required for the full steroidogenic response to cyclic AMP. Proc Natl Acad Sci U S A 113:E5685-93
Bornfeldt, Karin E (2016) Does Elevated Glucose Promote Atherosclerosis? Pros and Cons. Circ Res 119:190-3
Han, Chang Yeop (2016) Roles of Reactive Oxygen Species on Insulin Resistance in Adipose Tissue. Diabetes Metab J 40:272-9
Monette, Jeffrey S; Hutchins, Patrick M; Ronsein, Graziella E et al. (2016) Patients With Coronary Endothelial Dysfunction Have Impaired Cholesterol Efflux Capacity and Reduced HDL Particle Concentration. Circ Res 119:83-90
Ronsein, Graziella E; Reyes-Soffer, Gissette; He, Yi et al. (2016) Targeted Proteomics Identifies Paraoxonase/Arylesterase 1 (PON1) and Apolipoprotein Cs as Potential Risk Factors for Hypoalphalipoproteinemia in Diabetic Subjects Treated with Fenofibrate and Rosiglitazone. Mol Cell Proteomics 15:1083-93
Han, Chang Yeop; Tang, Chongren; Guevara, Myriam E et al. (2016) Serum amyloid A impairs the antiinflammatory properties of HDL. J Clin Invest 126:266-81
Tang, Chongren; Liu, Yuhua; Yang, Wendy et al. (2016) Hematopoietic ABCA1 deletion promotes monocytosis and worsens diet-induced insulin resistance in mice. J Lipid Res 57:100-8
Schulze, P Christian; Drosatos, Konstantinos; Goldberg, Ira J (2016) Lipid Use and Misuse by the Heart. Circ Res 118:1736-51

Showing the most recent 10 out of 95 publications