Neuronal Apoptosis: Overcoming Cytochrome c Limitations

神经元凋亡：克服细胞色素 c 的限制

• 批准号: 7222939
• 负责人: Allyson E VAUGHN
• 金额: $ 2.66万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-22 至 2008-12-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7222939
• 关键词: Apoptosis; Apoptotic; BIRC4 gene; Binding; Brain; Caspase; Caspase Inhibitor; Cell Death; Cells; Cessation of life; Cleaved cell; Complex; Condition; Cytosol; DNA Damage; Data; Development; Disease; Employee Strikes; Endopeptidases; Event; Fellowship; Fibroblasts; Individual; Injury; Localized; Mammalian Cell; Messenger RNA; Microinjections; Mitochondria; Mitotic; Names; Nerve Growth Factor 1; Nerve Growth Factor Pathway; Nerve Growth Factors; Neurodegenerative Disorders; Neurons; Pathway interactions; Peptide Hydrolases; Protein Overexpression; Proteins; Rate; Recruitment Activity; Regulation; Resistance; Signal Transduction; Spinal cord injury; Stimulus; Stress; Stroke; Testing; Translations; apoptotic protease-activating factor 1; base; caspase-3; caspase-9; cytochrome c; deprivation; neuron apoptosis; novel; prevent; pro-caspase-9; protein degradation; response

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.

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一个关键事件是细胞色素c从线粒体释放到细胞质中。然而，我们的初步数据表明，虽然细胞色素c的内源性释放可以很容易地诱导有丝分裂细胞的凋亡，但在交感神经元中并不足以这样做。此外，我们发现，与有丝分裂成纤维细胞相比，神经元中细胞色素c蛋白的水平显著低，但有趣的是，细胞色素c mRNA的水平却没有显著低。我们的假设是，交感神经元对内源性细胞色素c释放的抵抗是由于神经元中细胞色素c水平低。本研究的目的是：1)研究细胞色素c水平是否限制了神经元的凋亡，并确定细胞色素c水平是否在细胞凋亡刺激下增加。2)验证SM-20（在凋亡神经元中被诱导）是通过增加细胞色素c水平来允许神经元凋亡的假设。3)探讨细胞色素c在有丝分裂细胞和有丝分裂后神经元中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。