MITOCHONDRIAL COMMUNICATION IN CHEMICAL APOPTOSIS

化学凋亡中的线粒体通讯

• 批准号: 6573677
• 负责人: JOHN D ROBERTSON
• 金额: $ 0.55万
• 依托单位: KAROLINSKA INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-29 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6573677
• 关键词: BCL2 gene /protein; DNA damage; antisense nucleic acid; apoptosis; cysteine endopeptidases; cytochrome c; cytoprotection; enzyme activity; etoposide; heat shock proteins; high performance liquid chromatography; intracellular transport; laboratory rat; mitochondria; protein purification; western blottings

Nuclear biochemical changes that are characteristic of apoptosis and can be induced by a variety of cytotoxic stimuli are traditionally associated with the executive or late stages of this form of cell death. The long-term objective of this proposal is to advance our understanding of nuclear participation in the initiative or early stages of apoptosis. The main hypothesis to be studied is that DNA-damaging agents stimulate apoptosis by imparting changes at the nuclear level, resulting in the release of factors into the cytosol, which target mitochondria and stimulate the release of cytochrome c. Because of the apparent ability of Hsp27 to exert its anti-apoptotic effect against a variety of stimuli, including DNA-damaging agents, at the level of cytochrome c release, the mechanism regulating the cytoprotective potential of this protein is a complementary focus of this proposal. The specific aims are: 1) To characterize the ability of nuclei to stimulate established mitochondrial changes typical of apoptosis in response to DNA-damaging agents and the ability of Bcl-2/Bcl-XL to mitigate this effect; 2) To determine the mechanism(s) regulating the ability of Hsp27 to prevent apoptosomal caspase activation by blocking cytochrome c release. Completion of these studies will help clarify the ability of nuclear events, induced by DNA damage, to evoke mitochondrial changes characteristic of apoptosis and the mechanism responsible for Hsp27-mediated cytoprotection at the mitochondrial level.

细胞凋亡的特征性核生化变化可由多种细胞毒性刺激诱导，传统上与这种形式的细胞死亡的执行或晚期阶段相关。这项建议的长期目标是促进我们对细胞核参与细胞凋亡的主动或早期阶段的理解。待研究的主要假设是DNA损伤剂通过在核水平上赋予变化来刺激细胞凋亡，导致因子释放到细胞溶质中，其靶向线粒体并刺激细胞色素c的释放。由于Hsp 27在细胞色素c释放水平上对各种刺激物（包括DNA损伤剂）发挥其抗凋亡作用的明显能力，调节这种蛋白质的细胞保护潜力的机制是该提议的补充焦点。具体目标是：1）表征细胞核响应于DNA损伤剂刺激已建立的典型凋亡的线粒体变化的能力以及Bcl-2/Bcl-XL减轻这种作用的能力; 2）确定调节Hsp 27通过阻断细胞色素c释放来防止线粒体半胱天冬酶活化的能力的机制。这些研究的完成将有助于澄清核事件的能力，诱导的DNA损伤，引起线粒体的变化特征的细胞凋亡和机制负责热休克蛋白27介导的细胞保护在线粒体水平。