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.
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