CPLA2 MEDIATED CELL DEATH AND BC1-2 REGULATION

候选人亚当·萨皮尔斯坦接受过麻醉和 马萨诸塞州综合医院的重症监护医学。他的 临床上对危重疾病感兴趣，尤其是 急性肾功能衰竭。自1994年结束临床培训以来， 他在美国进行了一项密集的研究训练计划 约瑟夫·V·邦文垂博士的实验室。的长期目标是 候选人将独立研究急性胰腺炎的发病机制。 改善慢性肾功能衰竭患者的治疗和预后 这种病。磷脂酶活性的增加与此有关 在许多情况下的细胞损伤和死亡，包括：缺血 再灌流、氧化应激、炎症和败血症。这 项目~S的总体目标是确定 胞浆磷脂酶A2对细胞损伤的增强作用 (CPLA2)，并评估细胞如何保护自己免受cPLA2- 居间伤害。有伤害和保护意志的机制 对细胞死亡的一般机制有重要的见解。这个 为实现这些目标而提出的具体目标如下：具体目标1. 确定核膜破裂和酶激活 是cPLA2介导的H202增强的机制- 诱导肾上皮细胞死亡。具体目标2.至 确定cPLA2表达是否可以增加细胞的转录 受体介导的bcl2基因在肾上皮细胞的表达 互动。去寻找其他转录的基因 受cPLA2调控。具体目标3.确定肾脏的特征 大鼠肾缺血/再灌注损伤的发生及反应 CPLA2基因缺陷转基因小鼠(cPLS2基因敲除小鼠)。 提出了利用基本单元实现特定目标的方法 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。了解以下内容 CPLA2介导细胞损伤及cPLA22调控的机制 基因转录将导致对一般情况的重要见解 细胞死亡的机制，并将提供范例 CPLA2已处于临床状态的预防和治疗 与细胞和组织损伤有关。环境就是 马萨诸塞州总医院约瑟夫博士诉邦文垂实验室 医院。Bonventre博士是一名资深调查员， 对急性肾功能衰竭有兴趣的人 具有不同兴趣的研究员。候选人有 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 制度资源。

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.