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

系统性自身免疫性疾病（如系统性红斑狼疮（SLE））患者发生早发性心血管疾病（CVD）的风险增加，CVD是该患者人群发病率和死亡率的主要原因。临床研究已经强调了SLE患者血管疾病的证据，如内皮功能障碍和动脉僵硬，这使他们易于发生血管病变，但导致内皮功能障碍的起始因素尚不清楚。本项目的中心目标是确定导致SLE血管功能障碍发展的因素。为了实现这一目标，将使用SLE的临床相关模型，雌性NZBWF 1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博士先前的研究表明，与对照NZW小鼠相比，20周龄的NZBWF 1小鼠的内皮依赖性舒张功能受损，但自身抗体在介导内皮功能障碍中的作用尚不清楚。因此，具体目标1将检验SLE期间产生的致病性自身抗体导致SLE期间血管功能障碍的假设。Taylor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，在患者和NZBWF 1小鼠的SLE发病机制中存在肠道生态失调，这是一种微生物群组成改变的状况。虽然认识到肠道微生物组是重要的生理和免疫调节剂，但尚未确定肠道生态失调和血管功能障碍之间的机制联系。本提案的独立阶段将研究肠道生态失调导致SLE血管功能障碍的潜在机制。具体目标2将检验以下假设：循环细菌产物通过增加内皮和单核细胞TLR信号传导促进SLE中的内皮功能障碍，从而促进内皮细胞活化和损伤。第三个具体目标将检验在SLE中引入调节性T细胞（TREG）诱导细菌增加循环TREG和细胞因子IL-10和TGF-β以促进改善的血管功能的假设。将给予特定种类的细菌以改变肠道微生物组组成，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科学家，在学术界工作。她希望继续努力了解免疫系统与高血压和心血管疾病等慢性疾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，并将提高她的教学、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学和生物物理学系进行，该中心是高血压和心血管疾病领域的世界知名研究机构。

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.