CPLA2 MEDIATED CELL DEATH AND BC1-2 REGULATION

CPLA2 介导的细胞死亡和 BC1-2 调节

基本信息

批准号：
2015685
负责人：
ADAM SAPIRSTEIN
金额：
$ 8.99万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-15 至 2002-06-30
项目状态：
已结题

项目摘要

The candidate, Adam Sapirstein, was trained in anesthesia and critical care medicine at the Massachusetts General Hospital. His clinical interest is in diseases of critical illness and particularly acute renal failure. Since concluding his clinical training in 1994, he has undertaken an intensive research training program in the laboratory of Dr. Joseph V. Bonventre. The long term objective of the candidate is to independently investigate mechanisms of acute renal failure and improve the therapy and outcome for patients with this disease. Increased phospholipase activity has been implicated in cellular injury and death in many conditions including: ischemia and reperfusion, oxidant stress, inflammation and sepsis. This project~s broad objectives are to determine mechanisms of potentiation of injury induced by cytosolic phospholipase A2 (cPLA2) and to evaluate how cells protect themselves from cPLA2 - mediated injury. There mechanisms of injury and protection will yield important insights into general mechanisms of cell death. The specific aims proposed to achieve them are: Specific Aim 1. To determine if nuclear membrane disruption and enzyme activation are the mechanisms for cPLA2-mediated potentiation of H202- induced cell death in renal epithelia cells. Specific Aim 2. To determine if cPLA2 expression can increase the transcription of the bcl-2 gene in renal epithelial cells through a receptor-mediated gene interaction. To search for other genes that are transcriptionally regulated by cPLA2. Specific Aim 3. To characterize the renal development and response to renal ischemia/reperfusion of a transgenic mouse deficient in cPLA2 (cPLS2 knockout mouse). The methods proposed to achieve the specific aims utilize basic cell and molecular biological techniques that are currently in use in the Bonventre laboratory or in the labs of collaborators. Knowledge of mechanisms of cPLA2-mediate cell injury and cPLA22-regulated gene transcription will lead to important insights into general mechanisms of cell death, and will provide paradigms for prevention and treatment of clinical states in which cPLA2 has been implicated in cell and tissue injury. The environment is the laboratory of Dr. Joseph v. Bonventre at the Massachusetts General Hospital. Dr. Bonventre is an established senior investigator with an interest in acute renal failure who has successfully trained research fellows with a variety of interests. The candidate has established a productive scientific and clinical relationship within the lab and hospital and will be able to utilize the laboratory and institutional resources.

候选人亚当·萨皮斯坦 (Adam Sapirstein) 接受过麻醉方面的培训，马萨诸塞州总医院的重症监护医学。他的临床兴趣在于危重疾病，特别是急性肾功能衰竭。自 1994 年结束临床培训以来，他在以下领域进行了强化研究培训计划： Joseph V. Bonventre 博士的实验室。的长期目标候选人将独立研究急性发作的机制肾功能衰竭并改善患者的治疗和结果这种病。磷脂酶活性增加涉及多种情况下的细胞损伤和死亡，包括：以及再灌注、氧化应激、炎症和败血症。这项目的广泛目标是确定胞质磷脂酶 A2 诱导的损伤增强 (cPLA2) 并评估细胞如何保护自己免受 cPLA2 的侵害 - 介导的伤害。存在伤害和保护机制对细胞死亡的一般机制产生重要的见解。这为实现这些目标而提出的具体目标是：具体目标 1. 确定核膜是否破裂和酶激活是 cPLA2 介导的 H202- 增强作用的机制诱导肾上皮细胞死亡。具体目标 2. 至确定 cPLA2 表达是否可以增加 bcl-2 基因通过受体介导的基因存在于肾上皮细胞中相互作用。寻找其他转录基因受 cPLA2 调节。具体目标 3. 表征肾脏肾缺血/再灌注的发育和反应 cPLA2 缺陷转基因小鼠（cPLS2 敲除小鼠）。为实现特定目标而提出的方法利用基本细胞以及目前正在使用的分子生物学技术 Bonventre 实验室或合作者的实验室。知识 cPLA2介导的细胞损伤和cPLA22调节的机制基因转录将带来对一般现象的重要见解细胞死亡机制，并将提供范例 cPLA2已被用于临床状态的预防和治疗与细胞和组织损伤有关。环境是马萨诸塞州总医院 Joseph v. Bonventre 博士实验室医院。 Bonventre 博士是一位知名的高级研究员对急性肾功能衰竭感兴趣并已成功培训具有各种兴趣的研究员。候选人有在内部建立了富有成效的科学和临床关系实验室和医院，并将能够利用实验室和机构资源。