Moving Beyond HDL Cholesterol, HDL Function as a Coronary Disease Biomarker

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DESCRIPTION (provided by applicant): My career goal is to become an independent investigator focused on applying laboratory-based techniques assessing HDL functions to large human populations. I have focused thus far on acquiring clinical research skills allowing me to pursue broad epidemiologic assessments of novel biomarkers in improving coronary disease risk prediction in the Dallas Heart Study, culminating in several first-author publications and completion of a Master's Degree in Clinical Sciences. I am now positioned to apply this expertise to the biomarker area that I am most interested in-HDL function. My immediate research goals are based on evidence that directly assessing HDL functions in human studies may lead to better targeting of HDL-modifying therapies aimed at reducing cardiovascular disease (CVD) risk. These focused career goals mandate a mentored career development pathway to acquire the necessary laboratory-based skill sets to gain independence as a translational clinician investigator in the specific field of HDL metabolism and CVD. Key elements of my career development plan include: 1) multi-disciplinary mentorship: Dr. Philip Shaul as primary mentor, an established translational scientist, and Dr. James de Lemos as co-mentor, my current mentor in population science research and director of the Dallas Heart Study biomarker core; 2) coursework in laboratory and clinical research; 3) direct laboratory training in HDL function studies (Philip Shaul, UTSW; Dan Rader, Penn); and preparation for R01 grant application. The objective of this proposal is to systematically investigate two major HDL functions in relation to CHD in the general population. My central hypothesis is that plasma measurements of HDL-mediated macrophage-specific cholesterol efflux and HDL activation of eNOS (HDL functions) will vary significantly according to race, sex, and metabolic status and inversely correlate with vascular disease independent of HDL-C. I plan to test this hypothesis by prospectively measuring HDL function in an extensively phenotyped existing biobank of human plasma collected from the Dallas Heart Study (n=2,971; 50% African American; 50% women) to pursue the following three specific aims: 1) identify the biological factors influencing variation n HDL functions across a diverse population; 2) determine the associations of paraoxonase-1 (PON-1) activity and genotype with HDL functions; 3) comprehensively investigate the role of HDL functions in predicting CHD. These studies are anticipated to have an important positive impact, because the comprehensive assessment of the cardiovascular epidemiology of HDL function will rapidly facilitate clinical investigations targeting functional HDL pathways rather than simple concentration of HDL-C to reduce CHD risk. UT Southwestern combines extraordinary epidemiologic and translational research opportunities and faculty development programs that will ensure the PI's successful clinical research career, specifically the Dallas Heart Study led by Dr. Helen Hobbs, the Center for Nutrition led by Dr. Scott Grundy, and the Department of Clinical Sciences led by Dr. Milton Packer.