Mechanisms of apoptosis in the central nervous system

描述(申请人提供)：中枢神经系统(CNS)的病毒感染与多种神经系统疾病有关，包括脑膜炎、脑炎和脊髓炎，这些疾病的发病率和死亡率很高，成功的治疗方法有限。导致病毒诱导的细胞死亡、组织损伤和疾病的事件尚不清楚。因此，对嗜神经病毒杀死中枢神经系统细胞的机制的进一步了解是设计新的治疗策略的关键因素。细胞凋亡被认为是病毒诱导的中枢神经系统疾病的一种机制。在这项建议中，将研究病毒感染中枢神经系统后的细胞凋亡信号通路及其调控。呼肠孤病毒感染新生小鼠和培养的神经元，已被证明是研究中枢神经系统病毒发病机制的最重要的模型之一，将用于这些研究。病毒诱导的丝裂原活化蛋白激酶(特异性目标1)、转录因子(特异性目标2)和基因表达变化(特异性目标3)在呼肠孤病毒感染神经细胞后死亡受体和线粒体凋亡信号中的作用将被研究。在特定目标3中，除了靶向外，还将使用非靶向(微阵列分析)方法来阐明CNS发病的新的病毒机制。综上所述，这些研究旨在确定病毒诱导的中枢神经系统凋亡过程中凋亡信号的调节。它们有望对中枢神经系统疾病的新疗法的开发具有直接的治疗意义。

DESCRIPTION (provided by applicant): Viral infection of the central nervous system (CNS) is associated with a variety of neurologic diseases including meningitis, encephalitis, and myelitis, which have substantial morbidity and mortality and for which successful treatments are limited. The events that lead to virus-induced cell death, tissue injury and disease are not clearly understood. An increased understanding of the mechanisms by which neurotropic viruses kill cells in the CNS is thus a critical factor in the design of new therapeutic strategies. Apoptosis has been implicated as a mechanism of virus-induced CNS disease. In this proposal apoptotic signaling pathways and the regulation of these pathways will be investigated following viral infection of the CNS. Reovirus infection of neonatal mice and cultured neurons, which has proved to be one of the most important models for studying viral pathogenesis in the CNS, will be used for these studies. The role of virus-induced mitogen activated protein kinases (specific aim 1), transcription factors (specific aim 2) and gene expression changes (specific aim 3) will be investigated during death receptor and mitochondrial apoptotic signaling following reovirus infection of neuronal cells. In specific aim 3 non-targeted (microarray analysis), in addition to targeted, approaches will be used in order to elucidate novel viral mechanisms of CNS pathogenesis. Taken together these studies are designed to identify the regulation of apoptotic signaling during virus-induced apoptosis of the CNS. They are expected to have direct therapeutic implications for the development of novel therapies for CNS disease.