Diverse Roles of Interleukin 17 Isoforms in the Pathogenesis of Hypertension

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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.