CPLA2 MEDIATED CELL DEATH AND BC1-2 REGULATION

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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.