Diverse Roles of Interleukin 17 Isoforms in the Pathogenesis of Hypertension

白细胞介素 17 亚型在高血压发病机制中的多种作用

基本信息

批准号：
8617022
负责人：
Meenakshi Swaminathan Madhur
金额：
$ 12.54万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8617022
关键词：
Acute Adult Allergic Angiotensin II Antibodies Appointment Autoimmune Diseases Autoimmune Process Blood Pressure Blood Vessels CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cardiology Cardiovascular Diseases Cells Chronic Chronic Kidney Failure Clinical Pharmacology Clinical Trials Data Disease Doctor of Philosophy Drug Targeting Endothelial Cells Environment Etiology FDA approved Faculty Fellowship Functional disorder Funding Gene Expression General Population Genetic Goals Grant Helper-Inducer T-Lymphocyte Homologous Gene Human Human Resources Hypertension IL17 gene IL4 gene IL5 gene Immune Immune system Immunology Impaired Renal Function Individual Infiltration Inflammation Inflammatory Inflammatory Response Infusion procedures Injury Interferon Type II Interleukin-12 Interleukin-17 Interleukins Internal Medicine Kidney Knockout Mice Laboratories Lead Mediating Medical Mentors Mentorship Morbidity - disease rate Multiple Sclerosis Mus Nephrology Nuclear Organ Pathogenesis Pathway interactions Pharmaceutical Preparations Play Postdoctoral Fellow Production Protein Isoforms Psoriasis Reactive Oxygen Species Regulation Renal function Research Research Personnel Residencies Resources Rheumatoid Arthritis Risk Factors Role Scientist Serum Smooth Muscle Myocytes Societies Stroke Structure Superoxides T-Lymphocyte Th1 Cells Th2 Cells Therapeutic Time Training Training Programs Universities Vascular Diseases Virginia Widespread Disease base blood pressure regulation career career development cytokine hypertension control hypertension treatment inhibiting antibody insight interest kidney vascular structure meetings member mortality neutralizing antibody new therapeutic target normotensive novel professor public health relevance receptor response vascular inflammation

项目摘要

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.

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部门的新助理教授。她从弗吉尼亚大学医学科学家培训项目获得医学博士/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金。在埃默里大学 David Harrison 博士的实验室进行博士后研究期间，她对免疫系统在高血压中的作用产生了兴趣。新的证据表明高血压是一种炎症性疾病。 Madhur 博士是第一个证明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发挥关键作用的人。此外，她还发现，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 种亚型，分别命名为 IL17A 至 F，其中 IL17A 和 F 在结构、功能和表达方面关系最密切。 IL17A 缺陷小鼠中 IL17F 水平升高，表明协调调节，但 IL17F 在高血压中的作用尚不清楚。作为助理教授，在 Harrison 博士的持续指导下，申请人计划结合基因敲除小鼠和 IL17 及相关细胞因子的中和抗体，进一步研究白细胞介素 17 通路在高血压和相关终末器官功能障碍中的作用。她的初步数据表明，与 IL17A 相反，IL17F 可能在高血压和相关炎症反应中发挥保护作用。这一发现令人兴奋，并且在识别基于特定抗体的药物靶标方面具有重要的治疗意义。高血压。当前提案的重点之一是确定 IL17 亚型对高血压肾功能障碍的影响。为了协助该项目的这方面工作，她选择了一位联合导师雷蒙德·哈里斯 (Raymond Harris) 博士，他是范德比尔特大学肾脏病学主任，在急性和慢性肾损伤机制方面拥有专业知识。该提案中概述的研究将扩大我们对高血压病理生理学的理解，并有可能确定这种广泛疾病的新治疗靶点。 Madhur 博士目前的学术任命提供 80% 受保护的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研究。她聘请了一名博士后研究员，该研究员将协助她完成中概述的项目这笔补助金。范德比尔特大学为早期职业发展提供了卓越的研究和智力环境。申请人的培训计划包括教学课程、实验室会议、大学研讨会、全国会议、参加范德比尔特学会以促进初级教员的保留和终身任职、指导委员会以及一对一的指导和两位导师的指导。 Madhur 博士的长期职业目标是将自己打造成连接高血压和免疫学领域的独立临床医生兼研究者。