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

患有系统性红斑狼疮(SLE)等系统性自身免疫性疾病的患者发生过早心血管疾病(CVD)的风险增加，CVD是该患者群体发病率和死亡率的主要贡献者。临床研究强调了SLE患者存在血管疾病的证据，如内皮功能障碍和动脉僵硬，这使他们容易发生血管病变，但导致内皮功能障碍的启动因素尚不清楚。该项目的中心目标是确定导致系统性红斑狼疮血管功能障碍发展的因素。为了实现这一目标，将利用临床上相关的SLE模型，雌性NZBWF1小鼠。SLE小鼠和SLE患者都会产生自身抗体，介导组织损伤并导致终末器官损伤。导师Michael Ryan博士之前的研究表明，与对照NZW小鼠相比，20周大的NZBWF1小鼠已经损害了内皮依赖的松弛，但自身抗体在介导内皮功能障碍中的作用尚不清楚。因此，特殊目的1将检验假设，即在SLE过程中产生的致病自身抗体会导致SLE过程中的血管功能障碍。泰勒博士将接受实验室技术方面的额外培训，包括血管反应性研究和肠道微生物组分析。最近的研究表明，肠道微生物群组成改变的状况，与SLE患者和NZBWF1小鼠的发病机制有关。虽然人们认识到肠道微生物群是一种重要的生理和免疫调节因子，但肠道菌群失调和血管功能障碍之间的机制联系尚未确定。该提案的独立阶段将研究肠道生物失调导致系统性红斑狼疮血管功能障碍的潜在机制。特定目标2将验证这一假说，即循环细菌产物通过增加内皮和单核细胞TLR信号，促进内皮细胞的激活和损伤，从而促进SLE的内皮功能障碍。第三个具体目标将检验这样一个假设，即在系统性红斑狼疮中引入调节性T细胞(Treg)诱导细菌会增加循环中的Treg以及细胞因子IL-10和转化生长因子β，以促进血管功能的改善。将使用特定种类的细菌来改变肠道微生物群的组成，并分析增加Treg对血管功能的影响。泰勒博士的职业目标是成为一名独立的、多产的科学家，并在学术界开展工作。她希望继续致力于了解免疫系统与高血压和心血管疾病等慢性病的病理生理学之间的关系。在培训期间，泰勒博士将通过接受正式培训来提高她的实验室技能，还将提高她的教学、指导以及书面和口头沟通技能。这些培训活动将主要在密西西比大学医学中心的生理和生物物理系进行，该中心是世界著名的高血压和心血管疾病领域的研究机构。

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.