Diverse Roles of Interleukin 17 Isoforms in the Pathogenesis of Hypertension

简介（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部门的新助理教授。她获得了弗吉尼亚大学医学科学家培训计划的医学博士学位，并在杜克大学完成了内科住院医师实习，随后在埃默里大学获得了心脏病学研究奖学金。在埃默里大学大卫·哈里森博士的实验室做博士后期间，她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。Madhur博士首次证明了促炎细胞因子白细胞介素17A （IL17A）在血管紧张素II诱导的高血压和血管功能障碍中的关键作用。此外，她还表明，与血压正常的人相比，高血压患者的血清IL17A水平升高。IL17有6种同工异构体，分别命名为IL17A - F，其中IL17A和F在结构、功能和表达上关系最为密切。IL17F水平在IL17A缺陷小鼠中升高，提示协同调节，但IL17F在高血压中的作用尚不清楚。作为助理教授，申请人计划在Harrison博士的继续指导下，利用基因敲除小鼠和IL17及相关细胞因子的中和抗体的组合，进一步研究白细胞介素17通路在高血压及相关终末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炎症反应中起保护作用。这一发现令人兴奋，并具有重要的治疗意义，在确定特异性抗体为基础的药物靶点

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.