Mechanisms of virus-induced apoptosis in neurons and CNS

中枢神经系统(CMS)病毒感染是由于病毒损伤神经元和其他 大脑和脊髓内的非神经细胞。一种共同的机制，通过这种机制，不同的群体 嗜神经性病毒对CMS靶细胞的损伤是通过细胞凋亡来实现的。尽管如此，人们对此知之甚少 导致病毒诱导神经细胞凋亡的确切机制和特定的细胞途径。 在这项建议中，我们将利用呼肠孤病毒感染原代神经元培养物和呼肠孤病毒的小鼠模型- 诱导脑炎研究病毒诱导神经细胞凋亡的细胞途径。我们 已有研究表明，死亡受体的凋亡信号与呼肠孤病毒感染的神经元有关 细胞凋亡。我们假设线粒体和内质网细胞都应激凋亡信号。 通路也是呼肠孤病毒诱导的神经细胞死亡的关键。在目标1中，我们将确定所扮演的角色 通过内质网(ER)和细胞应激(GADD)途径诱导呼肠孤病毒诱导的神经细胞凋亡 并对所涉及的因素进行表征。在目标2中，我们将确定线粒体和线粒体的作用 呼肠孤病毒诱导细胞凋亡的因素。最后，在目标3中，我们将测试操纵细胞凋亡的效果 呼肠孤病毒诱导的中枢神经系统感染的体内致病途径。建议的一个关键方面 研究是将在体外原代培养神经元的研究中获得的结果转化为 中枢神经系统病毒感染的活体模型。呼肠孤病毒感染之所以被选为这些研究的对象，是因为它是 最广泛表征的病毒诱导的细胞凋亡模型，并提供了一个大的前 现有的关于病毒的凋亡决定因素和所涉及的细胞通路的知识基础，如 也是一种易于使用的中枢神经系统细胞凋亡小鼠模型，允许快速测试在 细胞培养在中枢神经系统病毒病体内发病机制中的意义

Central nervous system (CMS) viral infections result from the capacity of viruses to injure neurons and other non-neuronal cells within the brain and spinal cord. A common mechanism by which a diverse group of neurotropic viruses injure target cells in the CMS is through apoptosis. Despite this fact, little is known about the precise mechanisms and specific cellular pathways leading to virus-induced apoptotic neural cell death. In this proposal we will utilize reovirus infection of primary neuronal cultures and a murine model of reovirus- induced encephalitis to examine the cellular pathways involved in virus-induced neuronal apoptosis. We have previously shown that death receptor apoptotic signaling contributes to reovirus-indced neuronal apoptosis. We hypothesize that both mitochondrial and endoplasmic reticulum cell stress apoptotic signaling pathways are also critical to reovirus-induced neuronal cell death. In Aim 1 we will determine the role played by endoplasmic reticulum (ER) and cellular-stress (GADD) pathways on reovirus-induced neuronal apoptosis and characterize the factors involved. In Aim 2 we will determine the role of mitochondria and mitochondrial factors in reovirus-induced apoptosis. Finally, in Aim 3 we will test the effects of manipulating apoptotic pathways on the pathogenesis of reovirus-induced CNS infection in vivo. A key aspect of the proposed studies is the ability to translate results obtained in studies of primary neuronal cultures in vitro, into an in vivo model of CNS viral infection. Reovirus infection was selected for these studies because it is one of the most extensively characterized models of virus-induced apoptosis and offers the advantage of a large pre- existing base of knowledge concerning viral determinants of apoptosis and the cellular pathways involved, as well as an easily accessible in mouse model of CNS apoptosis that allows rapid testing of results obtained in cell culture for their significance on the pathogenesis of CNS viral disease in vivo