NEUROTROPHIC FACTOR DEPRIVATION AND NEURONAL CELL DEATH

神经营养因子剥夺和神经元细胞死亡

• 批准号: 6126266
• 负责人: LLOYD A GREENE
• 金额: $ 36.6万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6126266
• 关键词: DNA damage; PC12 cells; apoptosis; cyclin dependent kinase; cysteine endopeptidases; neurons; neurotrophic factors; oxidative stress; phosphorylation; tissue /cell culture; transcription factor

DESCRIPTION: The overall goal of this work is to understand the molecular pathways by which mammalian neurons undergo apoptotic death. The overall hypotheses are that the pathways of neuronal apoptotoic death are composed of multiple, causally-linked steps and that the nature of these steps depends on the initiating causes of death. The major focus will concern apoptosis evoked by trophic factor deprivation. Two additional means of evoking apoptosis will be considered for purposes of comparison, exposure to DNA damaging agents and induction of oxidative stress by depletion of superoxide dismutase 1. Studies will be performed in cultures of rat PC12 cells and sympathetic neurons. The proposed specific aims focus on two components of the apoptotic pathway. The hypothesis will be tested that apoptosis initiated by trophic factor deprivation and DNA damage (and not oxidative stress) requires activation of specific cyclin-dependent kinases, enhanced phosphorylation of Rb protein and activation of E2F transcription factors. The second aim focuses on the roles of members of the caspase family of cysteine aspartases as executors of neuronal apopototic death. Experiments will identify the caspases required for death in each of the three experimental apopotic paradigms, determine the means by which caspases are activated in response to apoptotic stimuli, and uncover the relative positions of the caspases to one another and to other elements in the apoptotic pathway. The hypothesis will be evaluated that neuronal apoptosis evoked by different causes is mediated by distinct caspase family members.

描述：这项工作的总体目标是了解分子