MITOCHONDRIAL COMMUNICATION IN CHEMICAL APOPTOSIS

核生化变化是细胞凋亡的特征，可由各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有关。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性或早期阶段的理解。研究的主要假设是dna损伤剂通过在核水平上施加改变来刺激细胞凋亡，导致因子释放到细胞质中，这些因子靶向线粒体并刺激细胞色素c的释放。由于Hsp27明显能够在细胞色素c释放水平上对包括dna损伤剂在内的多种刺激发挥其抗凋亡作用，调节该蛋白的细胞保护潜能的机制是本提案的补充重点。具体目的是：1)研究细胞核在dna损伤剂作用下刺激线粒体凋亡的能力，以及Bcl-2/Bcl-XL减轻这种影响的能力；2)探讨Hsp27通过阻断细胞色素c释放抑制凋亡体caspase活化的机制。这些研究的完成将有助于阐明DNA损伤诱导的核事件引起线粒体凋亡特征变化的能力，以及hsp27介导的线粒体水平细胞保护的机制。

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.