Cellular repair in acute kidney injury

急性肾损伤的细胞修复

• 批准号: 8598070
• 负责人: LISA M CURTIS
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598070
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Aging; Alabama; Animal Model; Animals; Binding; Biochemical Markers; Biochemistry; Biological Assay; Biology; Cell physiology; Cells; Cellular biology; Chronic; Chronic Kidney Failure; Clinical; Complement; Development; Development Plans; Dialysis procedure; Dose; Educational workshop; End stage renal failure; Environment; Epithelium; Feedback; Functional disorder; Genetic; Goals; Growth Factor; Hepatocyte Growth Factor; Histologic; Human; Immunohistochemistry; Individual; Injury; Innovative Therapy; K-Series Research Career Programs; Kidney; Kidney Papilla; Medical center; Medicine; Mentors; Mentorship; Microbiology; Modality; Molecular; Molecular Biology; Monitor; Morbidity - disease rate; Natural regeneration; Nephrology; Outcome; Papillary; Pathway interactions; Patients; Physicians; Physiology; Population; Process; Recovery; Recruitment Activity; Renal function; Renal tubule structure; Reperfusion Injury; Research; Research Personnel; Risk; Role; Secondary to; Severities; Signal Pathway; Signal Transduction; Site; Source; Stromal Cell-Derived Factor 1; Supplementation; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training; Transgenic Animals; Translations; Universities; Veterans; Work; base; career development; cell motility; chemokine; clinical care; clinically relevant; experience; implantation; improved; in vivo; in vivo Model; inhibitor/antagonist; injured; injury and repair; insight; interstitial; interstitial cell; kidney cell; meetings; member; migration; model design; mortality; neutralizing antibody; novel; post-doctoral training; professor; programs; receptor; reconstitution; repaired; research study; response; response to injury; responsible research conduct; tongue papilla; tool

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.

描述（由申请人提供）： 该研究计划的主要目标是为申请人丽莎·柯蒂斯（Lisa M. Curtis）博士提供细胞信号传导和肾脏生理学和病理生理学的新培训，以扩大其研究工具，以成为独立的VA研究者。为了实现这一目标，柯蒂斯博士将在伯明翰VAMC的肥沃环境和伯明翰大学（UAB）的阿拉巴马大学，在伯明翰VAMC的肾脏局长和医学教授的负责人保罗·W·桑德斯（Paul W. Sanders）的赞助下进行培训。伯明翰VAMC的工作人员兼UAB医学教授兼肾脏科教授，以及UAB微生物学，生物化学和遗传学的微生物学教授Christopher A. Klug博士，将提供其他指导。博士。桑德斯（Sanders），阿加瓦尔（Agarwal）和克鲁格（Klug）在指导方面拥有丰富的经验，并在UAB的博士后培训期间共同为柯蒂斯（Curtis）提供了指导。他们每个人都有独特的专业知识，可以促进对柯蒂斯博士进行科学和专业培训，这是实现她的长期目标所必需的。 拟议的研究将是在用于研究信号通路的过程中训练申请人的基础，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，这是急性肾脏损伤（AKI）的两个已知病理生理学调节剂。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。 该提案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。该提案的总体假设是，肾脏修复细胞驻留在肾乳头的FSP1+细胞群中，并因响应特定因素，HGF和SDF-1而被招募到损伤部位。该提案分为两个特定目标。第一个目的是利用临床相关的动物模型的缺血再灌注损伤（IRI）的体内模型，旨在阐明从肾乳头上募集的重复细胞的身份和剂量反应，以响应受伤的组织的信号。这个目标利用转基因动物中Cre-Lox系统的强大技术来标记肾脏中的特定细胞种群，然后可以通过组织化学和免疫组织化学技术跟踪。第二个目的使用IRI来确定HGF和/或SDF-1信号传导对上皮的修复的影响。该目标通过使用中和抗体或药理学剂对这两种药物的信号传导途径进行干扰。与第一个目标相似，这个目标利用了标记的修复细胞的迁移和融合的结果。同样，将监控AKI伤害和修复的其他指标以进行改动。 职业发展计划包括参加UAB的研讨会，研讨会和其他教育培训机会，例如细胞信号的高级课程以及负责任的研究进行培训。申请人将与肾部门，VAMC和UAB肾脏科的高级成员互动。指导计划包括与她的三位导师的正式和非正式会议，共同进行，这为她作为独立调查员的培训提供了机会，并为她提供了有关她的专业和科学进步的反馈。该职业发展奖将大大提高申请人的专业发展，成为一名独立的VA调查员。