High-density lipoprotein (HDL) protects against atherosclerosis by removing excess cholesterol from arterial cells. HDL has also been proposed to function as an important Inhibitor of cellular inflammation and lipid oxidation in vivo. Moreover, inflammation has been proposed to convert HDL to a dysfunctional form that loses these cardioprotective effects and may even be pro-inflammatory. Two important pathways may Involve oxidative damage and changes in the relative balance of pro- and antioxidant proteins in HDL. During the first two years of the award, the PI has completed a highly structured career development plan to prepare him for transition to a fully independent investigator. During this time, he has published five first author papers in peer-reviewed journals, that have directly addressed the hypotheses raised in the original proposal. Importantly, he has obtained strong preliminary data in diabetic humans that the proposed mechanisms for generation of dysfunctional HDL are pathophysiologically relevant. In collaboration with translational investigators at the University of Washington, the PI has laid the groundwork for developing a research program centered on understanding the role of HDL in diabetic cardiovascular disease. Importantly, the proposed studies are completely Independent of that of his mentor. He also has accepted a faculty position with the University of Washington and the Department of Medicine has assigned him independent laboratory space and an office at the newly established Diabetes and Obesity Center of Excellence. During the next phase of the K99/R00 award, the PI will focus on two major goals: first, establishing a fully independent research program centered on diabetes and cardiovascular diseases. Second, obtaining NIH funding for his research studies. The long-term goal is to combat atherosclerosis by understanding the molecular mechanisms for generation of dysfunctional HDL in humans suffering from diabetes and other inflammatory conditions.

Public Health Relevance

The overall goal of this proposal is to test the hypothesis that apoA-l oxidation and changes in the protein cargo of HDL impair the anti-inflammatory and cardioprotective effects of HDL In humans suffering from diabetes. Uncovering the molecular actions of inflammatory HDL may lead to new diagnostic and therapeutic approaches to atherosclerosis and other inflammatory conditions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL091055-05
Application #
8293138
Study Section
Special Emphasis Panel (NSS)
Program Officer
Liu, Lijuan
Project Start
2010-08-20
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$249,000
Indirect Cost
$99,000
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Shao, Baohai; de Boer, Ian; Tang, Chongren et al. (2015) A Cluster of Proteins Implicated in Kidney Disease Is Increased in High-Density Lipoprotein Isolated from Hemodialysis Subjects. J Proteome Res 14:2792-806
Segrest, Jere P; Jones, Martin K; Shao, Baohai et al. (2014) An experimentally robust model of monomeric apolipoprotein A-I created from a chimera of two X-ray structures and molecular dynamics simulations. Biochemistry 53:7625-40
Shao, Baohai; Tang, Chongren; Sinha, Abhishek et al. (2014) Humans with atherosclerosis have impaired ABCA1 cholesterol efflux and enhanced high-density lipoprotein oxidation by myeloperoxidase. Circ Res 114:1733-42
Oda, Michael N; Budamagunta, Madhu S; Geier, Ethan G et al. (2013) Conservation of apolipoprotein A-I's central domain structural elements upon lipid association on different high-density lipoprotein subclasses. Biochemistry 52:6766-78
Shao, Baohai; Pennathur, Subramaniam; Heinecke, Jay W (2012) Myeloperoxidase targets apolipoprotein A-I, the major high density lipoprotein protein, for site-specific oxidation in human atherosclerotic lesions. J Biol Chem 287:6375-86
Shao, Baohai (2012) Site-specific oxidation of apolipoprotein A-I impairs cholesterol export by ABCA1, a key cardioprotective function of HDL. Biochim Biophys Acta 1821:490-501
Shao, Baohai; Heinecke, Jay W (2011) Impact of HDL oxidation by the myeloperoxidase system on sterol efflux by the ABCA1 pathway. J Proteomics 74:2289-99
Shao, Baohai; Tang, Chongren; Heinecke, Jay W et al. (2010) Oxidation of apolipoprotein A-I by myeloperoxidase impairs the initial interactions with ABCA1 required for signaling and cholesterol export. J Lipid Res 51:1849-58
Shao, Baohai; Pennathur, Subramaniam; Pagani, Ioanna et al. (2010) Modifying apolipoprotein A-I by malondialdehyde, but not by an array of other reactive carbonyls, blocks cholesterol efflux by the ABCA1 pathway. J Biol Chem 285:18473-84
Shao, Baohai; Oda, Michael N; Oram, John F et al. (2010) Myeloperoxidase: an oxidative pathway for generating dysfunctional high-density lipoprotein. Chem Res Toxicol 23:447-54

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