Mechanisms of virus-induced apoptosis in neurons and CNS

中枢神经系统（CMS）病毒感染由病毒损伤神经元和其他神经元的能力引起。 脑和脊髓内的非神经元细胞。一种共同的机制， 嗜神经病毒通过细胞凋亡损伤CMS中的靶细胞。尽管如此，人们对 导致病毒诱导的神经细胞凋亡的确切机制和特定的细胞途径。 在这个提议中，我们将利用呼肠孤病毒感染的原代神经元培养物和呼肠孤病毒的小鼠模型， 诱导的脑炎，以检查参与病毒诱导的神经元凋亡的细胞通路。我们 先前的研究表明，死亡受体凋亡信号有助于呼肠孤病毒诱导的神经元凋亡， 凋亡我们假设线粒体和内质网细胞都应激凋亡信号 通路对于呼肠孤病毒诱导的神经元细胞死亡也是关键的。在目标1中，我们将确定所扮演的角色 内质网（ER）和细胞应激（GADD）途径对呼肠孤病毒诱导的神经元凋亡的影响 并描述相关因素。在目标2中，我们将确定线粒体和线粒体膜的作用。 呼肠孤病毒诱导的细胞凋亡的因素。最后，在目标3中，我们将测试操纵细胞凋亡的影响。 在体内对呼肠孤病毒诱导的CNS感染的发病机制的途径。所提议的一个关键方面是 研究是将体外原代神经元培养研究中获得的结果转化为体外神经元培养的能力。 CNS病毒感染的体内模型。选择呼肠孤病毒感染用于这些研究，因为它是免疫缺陷病毒之一。 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， 现有的知识基础，有关病毒决定因素的细胞凋亡和细胞途径， 以及一种容易获得的CNS细胞凋亡小鼠模型，该模型允许快速测试在 细胞培养在中枢神经系统病毒性疾病发病机制中的意义

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