Neuronal Apoptosis Induced by DNA Damage

描述（由申请人提供）：神经元凋亡在正常脑发育和神经变性中起重要作用。最近的研究结果表明，在脑损伤后，这种类型的神经元死亡优先通过caspase激活的内在途径进行。线粒体细胞色素c（Cyto-c）释放到细胞质中在这一途径中起着核心作用。Cyto-c释放由Bcl-2家族的促凋亡成员介导，其在损伤的神经元中响应于DNA损伤而被诱导。另一方面，其他报告表明，Cyto-c从线粒体的释放不足以诱导内在的凋亡途径。尽管有Cyto-c释放，但该途径的进展受到细胞外信号调节蛋白激酶Erk 1/2的抑制，Erk 1/2能够阻断胱天蛋白酶-9的活化并通过胱天蛋白酶原-9的直接磷酸化促进细胞存活。 抑制凋亡神经元中这种保护机制的途径仍然未知。在这个应用程序中，我们提出了一个可能的DNA损伤之间的联系，从线粒体释放Cyto-C，去磷酸化和失活的促生存Erk 1/2，激活半胱天冬酶，和神经元死亡。我们的工作假设是，DNA损伤诱导的神经元凋亡的进展依赖于p53介导的特定的双特异性磷酸酶（DUSPs）的激活，能够促进通过选择性Erk 1/2失活的半胱天冬酶原-9的加工。如果我们的假设是正确的，神经元损伤后抑制DUSP活性一定是神经保护性的。为了解决这一假设，我们提出了2个相关的具体目标：（1）检查DUSP基因家族成员在体外和体内脑创伤后对DNA损伤的反应中的神经元表达;（2）评估诱导型DUSP在抑制Erk 1/2、caspase激活和神经元死亡中的作用。这项研究的结果可能会产生根本性的影响，确定新的治疗策略，为各种各样的急性和慢性神经退行性疾病的DNA损伤和p53依赖性细胞凋亡的神经元损失的贡献是非常显着的。

DESCRIPTION (provided by applicant): Neuronal apoptosis plays an essential role in normal brain development and neurodegeneration. Results of recent studies indicate that after brain injury this type of neuronal death preferentially proceeds through the intrinsic pathway of caspase activation. The release of mitochondrial cytochrome c (Cyto-c) to the cytoplasm plays a central role in this pathway. Cyto-c release is mediated by pro-apoptotic members of Bcl-2 family, which are induced in injured neurons in response to DNA damage. On the other hand, other reports indicate that the release of Cyto-c from mitochondria is not sufficient for the induction of the intrinsic apoptotic pathway. Despite of Cyto-c release, progression of this pathway is inhibited by the extracellular signal-regulated protein kinases Erk1/2 able to block activation of caspase-9 and promote cell survival by direct phosphorylation of procaspase-9. A pathway, which restrains this protective mechanism in apoptotic neurons, remains unknown. In this application we propose a possible link between DNA damage, the release of Cyto-c from mitochondria, dephosphorylation and inactivation of pro-survival Erk1/2, activation of caspases, and neuronal death. Our working hypothesis is that the progression of DNA damage-induced apoptosis in neurons depends on p53-mediated activation of specific dual specificity phosphatases (DUSPs) able to promote processing of procaspase-9 through selective Erk1/2 inactivation. If our hypothesis is correct, inhibition of DUSP activity after neuronal injury must be neuroprotective. To address the hypothesis, we propose 2 related Specific Aims: (1) To examine neuronal expression of DUSP gene family members in response to DNA damage in vitro and after brain trauma in vivo and (2) To assess a role for inducible DUSPs in inhibition of Erk1/2, caspase activation, and neuronal death. Results of this study may have fundamental impact on identifying novel treatment strategies for a wide variety of acute and chronic neurodegenerative conditions where the contribution of DNA damage and p53-dependent apoptosis to neuronal loss is highly significant.