This proposal describes a 5 year training program for the development of an academic career in rheumatology. The principal investigator has completed formal training in a rheumatology fellowship program, and has completed the coursework for a master's degree in clinical research methodology. The training program outlined in this proposal will build upon these clinical skills, and allow the candidate to develop a career as a translational researcher by incorporating the development of laboratory research skills, skills in epidemiology, and statistical data analysis. Dr. Bevra Hahn, a recognized leader in the field of lupus research, will mentor the scientific development of the principal investigator. As the Chief of Rheumatology at UCLA, Dr. Hahn has successfully trained numerous fellows, and has been a successful research mentor for several highly successful clinical and laboratory researchers. In addition, an advisory committee of five highly regarded medical researchers will provide scientific and career advice. The proposed research will investigate the role of novel lipid biomarkers such as pro-inflammatory HDL (piHDL) in the development of atherosclerosis (ATH) in SLE. The proposal aims to discover whether these novel biomarkers can be used to identify SLE patients at risk for ATH, and also whether abnormalities such as piHDL will provide targets for therapy and prevention of atherosclerosis.
The specific aims i nclude: 1) Determining the progression of carotid artery IMT and change in the number of plaques in a cohort of 300 female SLE patients followed for three years compared to 150 age and gender matched controls. 2) Determining whether piHDL partly explains higher rates of ATH in this cohort by: a) examining the association with atherosclerosis on carotid ultrasound at baseline, and b) by examining the association with the rate of progression ATH over three years. 3) Determining whether other lipid biomarkers are associated with ATH in SLE subjects, including oxidized LDL, Lp(a), and apoJ. 4). Determining whether specific abnormalities in components of HDL are associated with piHDL, and whether these components are also associated with ATH in SLE, including levels of apolipoprotein A1, PAF-AH, and serum amyloid a, and activity of paraoxonase activity and LCAT. 5). Developing a risk prediction model for ATH in SLE, including significant lipid biomarkers from aims 2,3, and 4. Traditional risk factors are unable to completely identify Lupus patients who will develop early atherosclerosis. This proposal will explore whether poorly functioning Pro-inflammatory HDL, a novel marker for ATH, may allow physicians to identify lupus patients at risk, and initiate treatment to prevent cardiovascular events. Targeting PiHDL with interventions that restore protective function to HDL might be considered for prevention of ATH in both lupus and non lupus patients.
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