The overall hypotheses of the Cardiovascular Complications and Diabetes Program Project are that (i) dysfunctional HDL increases the risk of cardiovascular disease in diabetes and the metabolic syndrome, and (ii) the increased glucose, triglycerides and systemic inflammation that characterize diabetes and the metabolic syndrome reduce HDL's cardio protective properties. We propose that the increased risk of cardiovascular disease (CVD) associated with these disorders can be understood, prevented, and treated only by increasing our knowledge of the factors that regulate HDL function and macrophage and adipocyte inflammatory phenotypes. HDL's contribution to CVD associated with diabetes and the metabolic syndrome has been largely overlooked, and we believe that a highly interactive and interdisciplinary group of investigators with extensive expertise in this area, such as ours, i needed to answer this question. The expertise of our team in different aspects pertaining to the overall hypotheses of this Program Project will ensure synergy and cross-fertilization between Projects, which is likely to markedly advance research in this important and timely area. The Program Project Grant consists of four Projects and three Core units: * Project 1: HDL Function and Oxidation in Diabetic Atherosclerosis - Jay W. Heinecke, MD, Project Leader * Project 2: Dyslipidemia and Atherosclerosis Regression - Ira J. Goldberg, MD, Project Leader and Edward A. Fisher, MD, PhD, Co-Investigator * Project 3: Adipose Tissue Inflammation and HDL Function - Alan Chait, MD, Project Leader * Project 4: Diabetes-induced Myeloid Cell Activation, HDL and Atherosclerosis - Karin E. Bornfeldt, PhD, Project Leader * Core A: Administrative Core - Karin E. Bornfeldt, PhD, Core Director, Alan Chait, MD, Co-Director * Core B: Quantitative and Functional HDL Core - Tomas Vaisar, PhD, Core Director * Core C: Tissue and Imaging Core - Kevin D. O'Brien, MD, Core Director

Public Health Relevance

The proposed studies will have important implications for the management of patients with diabetes and the metabolic syndrome, in whom the risk of premature cardiovascular disease remains a serious threat. The investigations will provide important and interrelated insights into biomarkers and fundamental mechanisms of diabetic vascular disease, which in the long-term will set the stage for the development of new therapeutic agents and pharmacological strategies designed to interrupt the devastating complications of diabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL092969-57
Application #
9691951
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Chen, Jue
Project Start
1997-03-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2021-04-30
Support Year
57
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Wall, Valerie Z; Barnhart, Shelley; Kanter, Jenny E et al. (2018) Smooth muscle glucose metabolism promotes monocyte recruitment and atherosclerosis in a mouse model of metabolic syndrome. JCI Insight 3:
Kanter, Jenny E; Kramer, Farah; Barnhart, Shelley et al. (2018) A Novel Strategy to Prevent Advanced Atherosclerosis and Lower Blood Glucose in a Mouse Model of Metabolic Syndrome. Diabetes 67:946-959
Yuan, Chujun; Hu, Jiyuan; Parathath, Saj et al. (2018) Human Aldose Reductase Expression Prevents Atherosclerosis Regression in Diabetic Mice. Diabetes 67:1880-1891
Rune, Ida; Rolin, Bidda; Lykkesfeldt, Jens et al. (2018) Long-term Western diet fed apolipoprotein E-deficient rats exhibit only modest early atherosclerotic characteristics. Sci Rep 8:5416
Shao, Baohai; Heinecke, Jay W (2018) Quantifying HDL proteins by mass spectrometry: how many proteins are there and what are their functions? Expert Rev Proteomics 15:31-40
Basu, Debapriya; Hu, Yunying; Huggins, Lesley-Ann et al. (2018) Novel Reversible Model of Atherosclerosis and Regression Using Oligonucleotide Regulation of the LDL Receptor. Circ Res 122:560-567
Scolaro, Bianca; Nogueira, Marina S; Paiva, Aline et al. (2018) Statin dose reduction with complementary diet therapy: A pilot study of personalized medicine. Mol Metab 11:137-144
Fang, Xiang; Dorcely, Brenda; Ding, Xi-Ping et al. (2018) Glycemic reduction alters white blood cell counts and inflammatory gene expression in diabetes. J Diabetes Complications 32:1027-1034
Wight, Thomas N (2018) A role for proteoglycans in vascular disease. Matrix Biol 71-72:396-420
Bornfeldt, Karin E; Kramer, Farah; Batorsky, Anna et al. (2018) A Novel Type 2 Diabetes Mouse Model of Combined Diabetic Kidney Disease and Atherosclerosis. Am J Pathol 188:343-352

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