Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic inflammation an immune dysregulation. Cardiovascular disease (CVD) is a significant comorbidity and important cause of mortality in SLE. Although traditional cardiovascular (CV) risk factors occur frequently in SLE, their presence alone fails to explain the prevalence of CVD in SLE, implying that disease-specific processes have proatherogenic effects. The search for """"""""lupus factors"""""""" contributing to CVD in SLE has been unsuccessful. Emerging evidence indicates that widespread protein modification occurring in DM by glycation may be central factor in the common complications of DM (e.g. CVD, nephropathy) by altering cellular structure and function. Although initially thought to arise from hyperglycemia, there is compelling evidence that these altered proteins, known as advanced glycation end products (AGE), arise from dyslipidemia and increased oxidative stress, which may explain why glycemic control fails to prevent end-organ damage in DM. AGE are elevated in DM, but are also increased in nonDM patjents with other inflammatory conditions. AGE levels, and decreased levels of its soluble receptor, sRAGE, predict CVD in both DM and nonDM populations. Like SLE, complement activation is increased in patients with DM, and is postulated to contribute to end-organ damage. Complement activation results in increased oxidative stress, which is associated with dyslipidemia and insulin resistance, and thus may promote increased AGE formation in SLE. Furthermore, glycation of omplement regulatory proteins has been demonstrated to amplify complement activation. Hence, protein glycation in SLE may create a vicious cycle perpetuating ongoing vascular damage by formation of AGE and continued disease activity by glycation of complement regulatory proteins. We postulate that AGE may be a 'lupus factor"""""""" in CVD, and will explore this hypothesis by the following:
Specific Aim 1. Determine the associations between oxidative stress and disease activity with levels of AGE and sRAGE in SLE.
Specific Aim 2. Determine the role of oxidative stress, AGE, and sRAGE in CVD in SLE. CVD will be defined by arterial vascular stiffness.
Specific Aim 3. Determine the associations between AGE and sRAGE with complement activation in SLE. Complement activation will be defined by the presence of cell-bound complement activation products (CB-CAPS). The proposed project will advance the applicant's career development in translational research by fostering skills in designing and implementing longitudinal studies, data collection, management, analysis and interpretation. Attaining the stated Specific Aims will advance our understanding of the interactions between inflammation and complement activation and their role in CVD in SLE.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Mentored Patient-Oriented Research Career Development Award (K23)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Witter, James
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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