Demyelinating Disease-Viral and Cellular Function

描述(申请人提供)：多发性硬化症(MS)是一种中枢神经系统(CNS)的炎症性脱髓鞘疾病。MS的病因和发病机制尚未阐明，但可能是多因素的，涉及遗传和环境因素。包括冠状病毒在内的几种病毒与脱髓鞘过程有关，是MS的候选环境诱因。小鼠冠状病毒(MHV)可在啮齿类动物中诱发类似MS的疾病。本研究的长期目标是以MHV为模型阐明病毒诱导的中枢神经系统脱髓鞘疾病的发病机制。虽然大量证据表明免疫系统在MHV诱导的脱髓鞘的发生和发展中起着重要作用，但直到最近还不清楚免疫系统是否绝对需要引发这种疾病。最近，使用RAG1基因敲除小鼠的研究表明，在缺乏成熟T和B细胞的情况下，MHV感染可以诱导脱髓鞘，这表明MHV诱导的中枢神经系统脱髓鞘不需要T和B细胞。这一发现使我们假设，MHV在中枢神经系统的感染通过病毒直接杀死少突胶质细胞而导致髓鞘的破坏。这一假说得到了先前观察到的亚急性脑脊髓炎MHV感染大鼠中枢神经系统中检测到大量凋亡的少突胶质细胞的支持。我们最近的发现也证实了MHV感染诱导培养的大鼠少突胶质细胞凋亡。然而，MHV感染导致少突胶质细胞凋亡和破坏的潜在机制尚不清楚。我们提出了两个具体目标来解决这些问题。我们将首先确定是什么病毒因素诱导了培养的少突胶质细胞的凋亡。然后，我们将阐明MHV诱导少突胶质细胞凋亡的分子机制。这些研究将确定参与MHV感染调节少突胶质细胞凋亡的成分和生化途径，并将为深入了解病毒诱导的中枢神经系统脱髓鞘疾病的机制提供依据。这些研究结果将有助于开发针对MS等脱髓鞘疾病的有效治疗干预措施。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). The etiology and pathogenesis of MS have yet to be elucidated but are probably multifactorial, involving both genetic and environmental factors. Several viruses including coronavirus have been associated with demyelinating processes and represent candidate environmental triggers of MS. The murine coronavirus (MHV) can induce an MS-like disease in rodents. The long-term goal of this research is to elucidate the mechanisms of virus-induced demyelinating diseases of the CNS by using MHV as a model. While a large body of evidence has revealed an important role of the immune system in the onset and development of MHV-induced demyelination, it has remained unclear until recently whether the immune system is absolutely required for triggering the disease. Recently, studies using RAG1 knockout mice demonstrated that MHV infection induced demyelination in the absence of mature T and B cells, indicating that both T and B cells are not required for MHV-induced CNS demyelination. This finding leads us to hypothesize that MHV infection in the CNS results in the destruction of the myelin sheath by direct viral killing of oligodendrocytes. This hypothesis is supported by previous observation that a significant number of apoptotic oligodendrocytes were detected in CNS of MHV-infected rat with subacute encephalomyelitis. It is also substantiated by our recent findings that MHV infection induced apoptosis in cultured rat oligodendrocytes. However, the underlying mechanisms by which MHV infection causes apoptosis and destruction of oligodendrocytes are not known. We propose two specific aims to address these questions. We will first determine what viral factors induce apoptosis in cultured oligodendrocytes. We will then elucidate the molecular mechanisms underlying MHV-induced apoptosis in oligodendrocytes. These studies will identify the components and biochemical pathways that are involved in regulation of oligodendrocyte apoptosis by MHV infection, and will provide insights into the mechanisms of virus-induced demyelinating diseases of the CNS. Findings from these studies will be helpful for the development of effective therapeutic intervention for demyelinating diseases such as MS.