Neuronal Apoptosis: Overcoming Cytochrome c Limitations

描述（由申请人提供）：在哺乳动物细胞中激活半胱天冬酶并诱导细胞凋亡的关键事件是细胞色素c从线粒体释放到胞质溶胶中。然而，我们的初步数据表明，虽然内源性释放的细胞色素c可以很容易地诱导有丝分裂细胞的凋亡，这是不够的，这样做的交感神经元。此外，我们发现细胞色素c蛋白的水平，但有趣的是，细胞色素c mRNA的水平，是惊人的低，在神经元相比，有丝分裂成纤维细胞。我们的假设是，交感神经元对细胞色素c内源性释放的抵抗是由于神经元中细胞色素c水平低。该提议的目的是：1）检查细胞色素c水平是否限制神经元中的细胞凋亡，并确定它们是否响应于细胞凋亡刺激而增加。2)以检验SM-20（其在凋亡神经元中被诱导）增加细胞色素c水平以允许神经元中的凋亡的假设。3)询问在有丝分裂细胞和有丝分裂后神经元中观察到的细胞色素c的差异表达是否是交感神经元中翻译减少或蛋白质周转增加的结果。

DESCRIPTION (provided by applicant): A critical event that activates caspases and induces apoptosis in mammalian cells is the release of cytochrome c from the mitochondria into the cytosol. However, our preliminary data indicate that while endogenous release of cytochrome c can readily induce apoptosis in mitotic cells, it is not sufficient to do so in sympathetic neurons. In addition, we find levels of cytochrome c protein, but interestingly not levels of cytochrome c mRNA, to be strikingly low in neurons as compared to mitotic fibroblasts. Our hypothesis is that a sympathetic neuron's resistance to the endogenous release of cytochrome c is due to low levels of cytochrome c in neurons. The aims of this proposal are: 1) to examine whether cytochrome c levels are limiting for apoptosis in neurons, and determine if they increase in response to apoptotic stimuli. 2) to test the hypothesis that SM-20 (which is induced in apoptotic neurons) is to increase cytochrome c levels to permit apoptosis in neurons. 3) to ask whether the differential expression of cytochrome c seen in mitotic cells and postmitotic neurons is a result of decreased translation or increased protein turnover in sympathetic neurons.