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.

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.