Cellular repair in acute kidney injury

描述(由申请人提供)： 该研究计划的主要目标是为申请者Lisa M.Curtis博士提供细胞信号以及肾脏生理学和病理生理学方面的新的强化培训，以扩展她的研究工具，目的是成为一名独立的退伍军人管理局研究员。为了实现这一目标，柯蒂斯博士将在伯明翰VAMC和阿拉巴马大学伯明翰分校(UAB)肥沃的环境中接受培训，由伯明翰VAMC肾科主任、伯明翰大学医学教授Paul W.Sanders医学博士赞助。其他指导将由伯明翰VAMC的专职医生Anupam Agarwal博士和UAB的医学教授兼肾脏科主任Christopher A.Klug博士和UAB的微生物学、生物化学和遗传学教授Christopher A.Klug博士提供。Sanders博士、Agarwal博士和Klug博士在导师方面拥有丰富的经验，并曾在柯蒂斯博士在UAB进行博士后培训期间联合为她提供导师。他们每个人都有独特的专业知识，帮助完成柯蒂斯博士的科学和专业培训，这是实现她的长期目标所必需的。建议的研究将作为培训申请者用于研究信号通路的基础，特别是应用于肝细胞生长因子(HGF)和基质细胞衍生因子1(SDF-1)的研究，这两个已知的急性肾损伤(AKI)细胞修复的病理生理学调节因子。此外，这些研究将扩大申请人在经典细胞和分子生物学方面的专业知识，重点是肾脏病理生理学。这一建议的科学目标是阐明能够重建肾小管的肾细胞的身份，以及诱导这种修复反应所需的信号。该方案的总体假设是肾修复细胞存在于肾乳头的Fsp1+细胞群中，并根据特定的因子HGF和SDF-1被招募到损伤部位。该方案分为两个特定目的。第一个目的是利用缺血再灌注损伤(IRI)的体内模型，这是一个临床相关的动物模型，旨在阐明从肾乳头招募的修复细胞对损伤组织信号的反应的特性和剂量反应。这一目的是利用转基因动物中强大的Cre-lox系统技术来标记肾脏中的特定细胞群，然后通过组织化学和免疫组织化学技术进行追踪。第二个目的是使用IRI来确定HGF和/或SDF-1信号的存在或不存在对上皮修复的影响。这一目的是通过使用中和抗体或药理学试剂来干扰这两种药物的信号通路。与第一个目标类似，这个目标利用标记的修复细胞迁移和合并的结果；此外，将监测AKI损伤和修复的其他指标是否有变化。职业发展计划包括参加UAB的研讨会、讲习班和其他教育培训机会，如细胞信号高级课程，以及负责任的研究工作培训。申请者将与肾科、VAMC和UAB肾脏科的高级成员进行互动。指导计划包括与她的三位导师单独和一起举行正式和非正式会议，这些会议为她提供机会，介绍她作为独立调查员接受的培训，并就她的专业和科学进展向她提供反馈。这一职业发展奖将极大地促进申请者成为一名独立的退伍军人管理局调查员的职业发展。

DESCRIPTION (provided by applicant): The primary goal of this research program is to provide the applicant, Dr. Lisa M. Curtis, with new and intensive training in cell signaling and renal physiology and pathophysiology to expand her research tools with the purpose of becoming an independent VA investigator. To achieve this goal, Dr. Curtis will train in the fertile environment of the Birmingham VAMC and the University of Alabama at Birmingham (UAB), under the sponsorship of Paul W. Sanders, MD, Chief, Renal Section of the Birmingham VAMC and a Professor of Medicine at UAB. Additional mentoring will be provided by Dr. Anupam Agarwal, a staff physician at the Birmingham VAMC and Professor of Medicine and Division Director of Nephrology at UAB, and Dr. Christopher A. Klug, a Professor of Microbiology, Biochemistry and Genetics at UAB. Drs. Sanders, Agarwal and Klug have extensive experience in mentorship and have previously jointly provided Dr. Curtis with mentorship during her postdoctoral training at UAB. They each have unique expertise to facilitate accomplishing the scientific and professional training of Dr. Curtis that is necessary to achieve her long-term goals. The proposed studies will be the basis for training the applicant in the process used to study signaling pathways, particularly as applied to the study of hepatocyte growth factor (HGF) and stromal cell-derived factor 1 (SDF-1) , two known modulators of the pathophysiology of cellular repair in acute kidney injury (AKI). Additionally, these studies will expand the applicant's expertise in classical cell and molecular biology with an emphasis on renal pathophysiology. The scientific goals of this proposal are to elucidate the identity of renal cells that are capable of reconstitution of renal tubules and the signaling necessary to induce this reparative response. The overall hypothesis of the proposal is that renal reparative cells reside in the Fsp1+ cell population of the renal papilla and are recruited to sites of injury in response to the specific factors, HGF and SDF- 1. The proposal is divided into two specific aims. The first aim utilizes an in vivo model of ischemia- reperfusion injury (IRI), a clinically relevant animal model, designed to elucidate the identity and dose-response of reparative cells that are recruited from the renal papilla in response to signals from the injured tissue. This aim utilizes the powerful technique of the Cre-lox system in transgenic animals to mark specific cell populations in the kidney, which can then be tracked by histochemical and immunohistochemical techniques. The second aim uses IRI to ascertain the impact of the presence or absence of signaling by HGF and/or SDF-1 on the repair of the epithelium. This aim uses interference in the signaling pathways of these two agents through the use of neutralizing antibodies or pharmacologic agents. Similar to the first aim, this aim utilizes the outcome of the migration and incorporation of the marked reparative cells; as well, other indicators of injury and repair in AKI will be monitored for alterations. The career development plan includes attendance at seminars, workshops and other educational training opportunities at UAB, such as an advanced course in cell signaling, as well as training in the responsible conduct of research. The applicant will interact with senior members of the Renal Section, VAMC and the UAB Division of Nephrology. The Mentoring Plan includes formal and informal meetings with her three mentors, individually and together, which provide opportunities to address her training as an independent investigator as well as providing her with feedback on her professional and scientific progress. This Career Development Award will greatly enhance the applicant's professional development towards becoming an independent VA investigator.