Default Pathway of Apoptosis in Acute Renal Failure

急性肾衰竭细胞凋亡的默认途径

• 批准号: 7454218
• 负责人: VIMAL PATEL
• 金额: $ 13.71万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7454218
• 关键词: Acute; Acute Kidney Failure; Apoptosis; Apoptosis Promoter; Award; Biology; Cell Death; Cells; Chicago; Development Plans; Down-Regulation; Event; Factor Analysis; Genes; Goals; Growth Factor; Illinois; In Vitro; Intervention; Kidney; Kidney Diseases; Kidney Failure; Maps; Mediating; Mediator of activation protein; Mentored Research Scientist Development Award; Molecular Biology; Molecular Models; Mus; Pathogenesis; Pathway interactions; Phase; Proximal Kidney Tubules; Range; Recovery; Relative (related person); Research; Rodent; Role; Scientist; Signal Pathway; Signal Transduction; Stimulus; Technology; Therapeutic; Training; Treatment Efficacy; Tubular formation; Universities; body system; career; cell injury; cytotoxic; improved; in vivo; instructor; tool; transcription factor

DESCRIPTION (provided by applicant): The overall objective of this research career award application is to understand the role of the default pathway of apoptosis in the pathogenesis of acute renal failure (ARF). The goal of this application is to provide additional training in the rodent acute renal failure model and molecular biology technology to facilitate the candidates transition to an independent scientist in the field of apoptotis research relating to kidney disease. Previous studies on the role of apoptosis in ARF have focused on cytotoxic stimuli as inducers of apoptosis. We suggest that apoptosis of renal tubular cells is due not only to direct cellular injury but also to a relative deficiency of survival factors. Moreover, we suggest that the therapeutic efficacy of growth factors in experimental ARF is mediated, in part, through suppression of cell death and the default pathway of apoptosis. We aim to approach these questions in two ways. An in vitro approach will elucidate the signaling pathways and/or intracellular mediators by which spontaneous activation of ERK1/2 in Mouse Kidney Proximal Tubule (MKPT) cells deprived of all soluble survival factors induces down-regulation of Akt and promotes MKPT cell apoptosis. Through the use of cell signaling and molcular biology tools, we will dissect the mechanism of this relationship and with the use of gene array and transcription factor analysis we will map the downstream events occurring during the default pathway of apoptosis. The in vivo approach will examine the role of the ERK1/2 pathway in recovery from experimental ischemic ARF agin using molcular approaches. Interventions that ameliorate apoptosis during the recovery phase of ARF have great therapeutic potential, since they can be administered after the onset of ARF without the need to anticipate when ARF will occur. The candidate, Vimal Patel, is an Instructor at the University of Illinois, Chicago and the training team of Jerrold Levine, David Ucker, Jose Arruda, David Basile, Wil Leiberthal, Mike Abecassis and John Schwartz consists of established experts in the apoptosis and acute renal failure fields. There is institutional commitment and a integrated career development plan encompasing a broad range of activities. Taken together these studies will improve our understanding of the default pathway in ARF and provide Dr. Patel the rigorous training needed to facilitate his goal of an independent research career. Moreover, these studies should also help in understanding the default pathway of apoptosis in other cell and organ systems.

描述(由申请人提供)： 这项研究生涯奖申请的总体目标是了解细胞凋亡的默认途径在急性肾功能衰竭(ARF)发病机制中的作用。这项申请的目标是在啮齿动物急性肾功能衰竭模型和分子生物学技术方面提供额外的培训，以促进候选人过渡到与肾脏疾病相关的细胞凋亡性研究领域的独立科学家。以往关于细胞凋亡在ARF中的作用的研究主要集中在细胞毒刺激作为细胞凋亡的诱导剂。我们认为，肾小管上皮细胞的凋亡不仅与细胞的直接损伤有关，也与生存因子的相对缺乏有关。此外，我们认为生长因子对实验性ARF的治疗作用部分是通过抑制细胞死亡和默认的细胞凋亡途径来实现的。我们的目标是通过两种方式解决这些问题。体外实验将阐明去除所有可溶性生存因子的小鼠肾脏近端小管(MKPT)细胞中ERK1/2的自发激活诱导Akt下调并促进MKPT细胞凋亡的信号通路和/或细胞内介质。通过使用细胞信号转导和分子生物学工具，我们将剖析这种关系的机制，并使用基因阵列和转录因子分析，我们将定位发生在默认的凋亡途径的下游事件。活体方法将检验ERK1/2通路在实验性缺血性ARF恢复中的作用。在ARF恢复期改善细胞凋亡的干预措施具有巨大的治疗潜力，因为它们可以在ARF发病后使用，而不需要预测ARF将发生的时间。候选人维马尔·帕特尔是芝加哥伊利诺伊大学的一名讲师，杰罗尔德·莱文、大卫·乌克、何塞·阿鲁达、大卫·巴西尔、威尔·莱伯塔尔、迈克·阿贝卡西斯和约翰·施瓦茨的训练团队由细胞凋亡和急性肾功能衰竭领域的资深专家组成。有机构承诺和涵盖广泛活动的综合职业发展计划。综上所述，这些研究将提高我们对ARF中默认途径的理解，并为Patel博士提供必要的严格培训，以促进他实现独立研究生涯的目标。此外，这些研究还应该有助于理解其他细胞和器官系统中的默认凋亡途径。