Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease marked by autoantibody production, glomerulonephritis, and vasculitis. The etiology of SLE is unknown, although a genetic predisposition coupled with an environmental trigger appear necessary for the development of disease. SLE occurs 3-4 times more often in African Americans than Caucasians and African Americans with lupus have greater morbidity and mortality primarily due to renal disease. We demonstrated higher nitric oxide (NO) production in patients with lupus compared to controls, that NO production correlates with disease activity, that polymorphisms in the inducible nitric oxide synthase gene (iNOS) are linked with disease in African American females and that African Americans, produce more NO than Caucasians. Our hypothesis is that NO is a pathogenic factor in SLE and that differential production of NO plays a role in the ethnic disparity in lupus. To address this hypothesis, the following specific aims are proposed:
Aim 1 A. Assay systemic NO and peroxynitrite (ONOO-) production in humans with SLE as an indicator of disease activity. Determine whether the association between NO and disease activity is evident in specific SLE subsets B. To assess potential mechanisms for NO pathogenesis in disease, we will measure renal eicosanoid/isoprostane excretion in parallel with NO measures. C. Assess in vitro effects of NO on eicosanoid production by PBMCs from lupus patients and controls. D. Assess renal expression of iNOS in renal biopsies from lupus patients correlating expression with renal outcome. ? ? Aim 2 A. Using the unique Carolina lupus (CLU) cohort, determine the association of lupus and specific disease manifestations/progression with polymorphisms in the promoter regions of the iNOS, eNOS and nNOS genes. B. Confirm the association of iNOS polymorphisms with lupus by TDT analysis of African American families from the Oklahoma Lupus Registry. C. Determine if there are differences in NO production/iNOS expression by stimulated PBMCs between SLE patients and controls with and without the NOS polymorphisms. ? ? Aim 3 A. Determine the mechanism for renal disease expression in MRL/lpr iNOS knockout mice compared to wild type MRL/lpr mice and MRL/lpr mice treated with iNOS inhibitors B. Assess effects of specific and nonspecific inhibitors of iNOS production on disease presentation in iNOS knockout MRL/lpr mice. C. Identify the proteins that are nitrated in the renal cortex of MRL/lpr mice using a proteomics approach.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR045476-04A1
Application #
6573248
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Gretz, Elizabeth
Project Start
1999-04-23
Project End
2008-02-29
Budget Start
2003-03-10
Budget End
2004-02-29
Support Year
4
Fiscal Year
2003
Total Cost
$295,611
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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Al Gadban, Mohammed M; German, Jashalynn; Truman, Jean-Philip et al. (2012) Lack of nitric oxide synthases increases lipoprotein immune complex deposition in the aorta and elevates plasma sphingolipid levels in lupus. Cell Immunol 276:42-51

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