Diverse Roles of Interleukin 17 Isoforms in the Pathogenesis of Hypertension

描述(由申请人提供)：申请人Madhur博士是范德比尔特大学临床药理学和心脏病学系的新助理教授。她获得了弗吉尼亚大学医学科学家培训项目的医学博士学位，并在杜克大学完成了内科住院医师资格，随后在埃默里大学获得了心脏病学研究奖学金。在埃默里的博士后研究期间，她在大卫·哈里森博士的实验室里，对免疫系统在高血压中的作用产生了兴趣。越来越多的证据表明，高血压是一种炎症性疾病。马德胡尔博士是第一个证明促炎细胞因子白介素17A(IL17A)在血管紧张素II诱导的高血压和血管功能障碍中起关键作用的人。此外，她还表明，与血压正常的人相比，患有高血压的人血清IL17A水平升高。IL17有6种亚型，命名为IL17A到F，其中IL17A和F在结构、功能和表达方面关系最为密切。在IL17A缺乏的小鼠中IL17F水平升高，提示协同调节，然而IL17F在高血压中的作用尚不清楚。作为一名助理教授，申请人计划在哈里森博士的持续指导下，利用基因敲除小鼠和IL17中和抗体及相关细胞因子，进一步研究IL 17途径在高血压和相关末端器官功能障碍中的作用。她有初步数据表明，与IL17A相反，IL17F可能在高血压和相关的炎症反应中起到保护作用。这一发现令人兴奋，并在识别基于抗体的特定药物靶点方面具有重要的治疗意义。 高血压。目前该提案的一个重点是确定IL17亚型对高血压患者肾功能障碍的影响。为了协助该项目的这一方面，她选择了一位共同导师雷蒙德·哈里斯博士，他是范德比尔特大学肾脏科主任，在急性和慢性肾脏损伤的机制方面拥有专业知识。这项提案中概述的研究将扩大我们对高血压的病理生理学的理解，并可能导致确定这种广泛存在的疾病的新治疗靶点。马德胡尔博士目前的学术任命提供了80%的受保护研究时间以及实验室空间、启动资金，以及获得核心资源和支持人员来开展拟议的研究。她已经聘请了一名博士后研究员，他将在 这笔赠款。范德比尔特为早期职业发展提供了卓越的研究和智力环境。申请者的培训计划包括授课课程、实验室会议、大学研讨会、全国会议、参与范德比尔特学会以促进初级教师的留任和终身教职、一个指导委员会，以及来自两位导师的一对一指导和指导。马德胡尔博士的长期职业目标是将自己确立为一名独立的临床医生兼研究员，在高血压和免疫学领域架起一座桥梁。

DESCRIPTION (provided by applicant): The applicant, Dr. Madhur, is a new Assistant Professor in the Divisions of Clinical Pharmacology and Cardiology at Vanderbilt University. She obtained her MD/PhD degrees from the University of Virginia Medical Scientist Training Program and completed her Internal Medicine residency at Duke University followed by a research track Cardiology Fellowship at Emory University. During her post-doctoral fellowship at Emory, in the laboratory of Dr. David Harrison, she became interested in the role of the immune system in hypertension. Emerging evidence indicates that hypertension is an inflammatory disease. Dr. Madhur was the first to demonstrate a critical role for the pro-inflammatory cytokine, interleukin 17A (IL17A), in angiotensin II induced hypertension and vascular dysfunction. Moreover, she showed that serum levels of IL17A were increased in humans with hypertension compared to normotensive individuals. There are 6 isoforms of IL17, designated IL17A through F, of which IL17A and F are most closely related in terms of structure, function, and expression. IL17F levels are increased in IL17A deficient mice, suggesting coordinate regulation, yet the role of IL17F in hypertension is unknown. As an Assistant Professor, under the continued mentorship of Dr. Harrison, the applicant plans to further investigate the role of the interleukin 17 pathway in hypertension and the associated end organ dysfunction using a combination of genetic knockout mice and neutralizing antibodies to IL17 and related cytokines. She has preliminary data that IL17F, contrary to IL17A, may serve a protective role in hypertension and the associated inflammatory response. This finding is exciting and has important therapeutic implications in terms of identifying specific antibody based drug targets for hypertension. One focus of the current proposal is to determine the effect of IL17 isoforms on renal dysfunction in hypertension. To assist in this aspect of the project, she has chosen a co-mentor, Dr. Raymond Harris, who is the Chief of Nephrology at Vanderbilt and has expertise in mechanisms of acute and chronic kidney injury. The studies outlined in this proposal will expand our understanding of the pathophysiology of hypertension and potentially lead to the identification of novel therapeutic targets for this widespread disease. Dr. Madhur's current academic appointment provides 80% protected research time as well as laboratory space, start-up funds, and access to core resources and support personnel to carry out the proposed studies. She has hired a post-doctoral fellow who will be assisting her on the projects outlined in this grant. Vanderbilt offers an exceptional research and intellectual environment for early career development. The applicant's training plan includes didactic courses, lab meetings, university seminars, national meetings, participation in Vanderbilt societies to promote the retention and tenure of junior faculty members, a mentoring committee, and one-on-one mentorship and guidance from both mentors. Dr. Madhur's long-term career goal is to establish herself as an independent clinician-investigator bridging the fields of hypertension and immunology.