Immune system dysfunction and gut dysbiosis in the pathogenesis of vascular dysfunction in autoimmunity

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Patients with systemic autoimmune diseases such as systemic lupus erythematosus (SLE) have an increased risk of developing premature cardiovascular disease (CVD), the chief contributor to morbidity and mortality in this patient population. Clinical studies have highlighted evidence of vascular disease in SLE patients, such as endothelial dysfunction and arterial stiffness, which predisposes them to the development of vascular lesions, but the initiating factors that cause endothelial dysfunction are unknown. The central goal of this project is to identify the factors that contribute to the development of vascular dysfunction in SLE. To accomplish this goal, a clinically relevant model of SLE, the female NZBWF1 mouse, will be utilized. Both SLE mice and patients with SLE produce autoantibodies that mediate tissue injury and lead to end-organ damage. Previous studies by the mentor, Dr. Michael Ryan, show that by 20 weeks of age, NZBWF1 mice have impaired endothelium-dependent relaxation as compared to control NZW mice, but the role of autoantibodies in mediating the endothelial dysfunction is unknown. Thus, specific aim 1 will test the hypothesis that pathogenic autoantibodies produced during SLE cause vascular dysfunction during SLE. Dr. Taylor will receive additional training in laboratory techniques, including vascular reactivity studies and gut microbiome analyses. Recent studies have implicated gut dysbiosis, a condition of altered microbiota composition, in the pathogenesis of SLE in both patients and the NZBWF1 mouse. While it is recognized that the gut microbiome is an important physiological and immunological regulator, a mechanistic link between gut dysbiosis and vascular dysfunction has not been identified. The independent phase of this proposal will examine potential mechanisms whereby gut dysbiosis contributes to vascular dysfunction in SLE. Specific aim 2 will test the hypothesis that circulating bacterial products promote endothelial dysfunction in SLE by increasing endothelial and monocytic TLR signaling, contributing to endothelial cell activation and damage. The third specific aim will test the hypothesis that introduction of regulatory T cell (TREG)-inducing bacteria in SLE increases circulating TREG and the cytokines IL-10 and TGF-β, to promote improved vascular function. Specific species of bacteria will be administered to alter the gut microbiome composition and analyze the effect of increasing TREG on vascular function. Dr. Taylor’s career goal is to become an independent productive scientist with a career in academia. She hopes to continue to work to understand the relationship between the immune system and the pathophysiology of chronic diseases such as hypertension and cardiovascular disease. During the training period, Dr. Taylor will improve her laboratory skills by receiving formal training and will also improve her teaching, mentoring, and written and oral communication skills. These training activities will primarily take place at the University of Mississippi Medical Center in the Department of Physiology and Biophysics, which is a world-renowned research institution in the fields of hypertension and cardiovascular disease.