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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AR053864-05
Application #
8078960
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Witter, James
Project Start
2007-06-15
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2011
Total Cost
$125,010
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Marsillach, Judit; Becker, Jessica O; Vaisar, Tomas et al. (2015) Paraoxonase-3 is depleted from the high-density lipoproteins of autoimmune disease patients with subclinical atherosclerosis. J Proteome Res 14:2046-54
McMahon, Maureen; Skaggs, Brian J; Grossman, Jennifer M et al. (2014) A panel of biomarkers is associated with increased risk of the presence and progression of atherosclerosis in women with systemic lupus erythematosus. Arthritis Rheumatol 66:130-9
Rullo, Ornella J; Woo, Jennifer M P; Parsa, Miriam F et al. (2013) Plasma levels of osteopontin identify patients at risk for organ damage in systemic lupus erythematosus. Arthritis Res Ther 15:R18
Skaggs, Brian J; Hahn, Bevra H; McMahon, Maureen (2012) Accelerated atherosclerosis in patients with SLE--mechanisms and management. Nat Rev Rheumatol 8:214-23
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McMahon, Maureen; Skaggs, Brian J; Sahakian, Lori et al. (2011) High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids. Ann Rheum Dis 70:1619-24
McMahon, Maureen; Hahn, Bevra H; Skaggs, Brian J (2011) Systemic lupus erythematosus and cardiovascular disease: prediction and potential for therapeutic intervention. Expert Rev Clin Immunol 7:227-41
Hahn, B H; Lourencço, E V; McMahon, M et al. (2010) Pro-inflammatory high-density lipoproteins and atherosclerosis are induced in lupus-prone mice by a high-fat diet and leptin. Lupus 19:913-7
Skaggs, Brian J; Hahn, Bevra H; Sahakian, Lori et al. (2010) Dysfunctional, pro-inflammatory HDL directly upregulates monocyte PDGFR*, chemotaxis and TNF* production. Clin Immunol 137:147-56
Volkmann, Elizabeth R; Grossman, Jennifer M; Sahakian, Lori J et al. (2010) Low physical activity is associated with proinflammatory high-density lipoprotein and increased subclinical atherosclerosis in women with systemic lupus erythematosus. Arthritis Care Res (Hoboken) 62:258-65

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