Anti-inflammatory properties of high-density lipoprotein

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DESCRIPTION (provided by applicant): It is widely believed that high-density lipoprotein (HDL) protects against atherosclerosis by removing excess cholesterol from arterial cells. In addition to HDL's role in cholesterol transport and removal, increasing evidences support its functions 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 cardio protective effects and may even be pro-inflammatory. The underlying factors that render HDL pro-inflammatory remain poorly understood. Two important pathways may involve oxidative damage and changes in the relative balance of pro- and antioxidant proteins in HDL. This proposal outlines a highly structured career development plan that will promote the transition of the applicant to a fully independent investigator. The major component of the proposal is intense exposure to basic science studies that will test the hypothesis that oxidation and changes in the protein cargo impair the anti inflammatory and cardio protective effects of HDL. The applicant will be mentored during the first two years of the award. This period of training will build upon his strong background in mass spectrometry and extend his expertise to model system studies, computational biology, and animal models of hypercholesterolemia. The applicant will also initiate translational studies that will use a proteomics approach to define the protein cargo of HDL. In the last three years of the award, the applicant will develop an independent research program centered on understanding the role of HDL in vascular wall biology, with an emphasis on murine models of inflammation and atherosclerosis. The long term goal is to establish the applicant as a fully independent biomedical investigator in an NIH-funded tenure-track position at an academic medical center.