MITOCHONDRIAL COMMUNICATION IN CHEMICAL APOPTOSIS

以细胞凋亡为特征的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有关。这一建议的长期目标是促进我们对核参与细胞凋亡的主动或早期阶段的理解。要研究的主要假设是DNA损伤剂通过在核水平传递变化来刺激细胞凋亡，导致因子释放到胞浆中，这些因子针对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损伤剂在内的各种刺激发挥抗凋亡作用，因此调节该蛋白的细胞保护潜力的机制是本提议的补充重点。其具体目的是：1)研究细胞核刺激DNA损伤剂引起的以细胞凋亡为特征的线粒体改变的能力，以及Bcl2/Bclxl减轻这种影响的能力；2)确定通过抑制细胞色素c的释放来调节Hsp27抑制凋亡体caspase激活的机制(S)。这些研究的完成将有助于阐明DNA损伤引起的核事件引起以细胞凋亡为特征的线粒体变化的能力，以及在线粒体水平上Hsp27介导的细胞保护的机制。

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.