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

项目摘要/摘要 系统性红斑狼疮(SLE)等系统性自身免疫性疾病的患者 患早产儿心血管疾病(CVD)的风险增加，这是发病率和 这一患者群体中的死亡率。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 损伤，但导致内皮功能障碍的启动因素尚不清楚。这样做的中心目标是 该项目旨在确定导致系统性红斑狼疮血管功能障碍发展的因素。至 为了实现这一目标，将利用与临床相关的SLE模型-雌性NZBWF1小鼠。两人都是系统性红斑狼疮 小鼠和系统性红斑狼疮患者会产生自身抗体，介导组织损伤并导致终末器官损伤。 这位导师迈克尔·瑞安博士之前的研究表明，到20周大时，NZBWF1小鼠已经受损 内皮依赖性松弛与对照组NZW小鼠相比，但自身抗体的调节作用 血管内皮细胞功能障碍尚不清楚。因此，特定目标1将检验致病的假设 系统性红斑狼疮期间产生的自身抗体会导致系统性红斑狼疮时血管功能障碍。泰勒博士将收到额外的 实验室技术培训，包括血管反应性研究和肠道微生物组分析。近期 研究表明，肠道菌群失调与系统性红斑狼疮发病有关。 在两个患者和NZBWF1小鼠中。虽然人们认识到肠道微生物群是一种重要的 生理和免疫调节剂，肠道生物失调和血管功能障碍之间的机制联系 目前还没有确定。这项提案的独立阶段将审查潜在的机制， 肠道生物失调是SLE血管功能障碍的原因之一。《特定目标2》将检验循环的假说 细菌制剂通过增加内皮细胞和单核细胞TLR促进SLE患者内皮功能障碍 信号，促进内皮细胞的激活和损伤。第三个具体目标将检验这一假设 调节性T细胞(Treg)诱导细菌在SLE中的引入增加循环Treg和细胞因子 IL-10和转化生长因子-β，促进血管功能改善。特定种类的细菌将被注射到 改变肠道微生物群组成，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 希望继续努力了解免疫系统和病理生理学之间的关系 慢性疾病，如高血压和心血管疾病。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，并将改善她的教学、指导和 良好的书面和口头沟通能力。这些培训活动将主要在华盛顿大学进行。 密西西比州医学中心生理和生物物理系，这是一项享誉世界的研究 在高血压和心血管疾病领域的研究机构。

PROJECT SUMMARY/ABSTRACT 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.