Demyelinating Disease-Viral and Cellular Function

脱髓鞘疾病-病毒和细胞功能

• 批准号: 6819298
• 负责人: Xuming Zhang
• 金额: $ 19.59万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6819298
• 关键词: Coronaviridae; apoptosis; cysteine endopeptidases; disease /disorder etiology; disease /disorder model; enzyme activity; gene environment interaction; host organism interaction; molecular pathology; multiple sclerosis; murine hepatitis virus; myelin; myelinopathy; oligodendroglia; pathologic process; protein structure function; tissue /cell culture; viral myelinopathy; virus cytopathogenic effect; virus infection mechanism; virus protein; yeast two hybrid system

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.

描述（由申请人提供）：多发性硬化症（MS）是中枢神经系统（CNS）的炎症性脱髓鞘疾病。 MS的病因和发病机理尚未阐明，但可能是多因素，既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，代表了MS的候选环境触发因素。鼠冠状病毒（MHV）可以在啮齿动物中诱导MS样疾病。这项研究的长期目标是通过使用MHV作为模型来阐明病毒诱导的CNS脱髓鞘疾病的机制。尽管大量证据揭示了免疫系统在MHV诱导的脱髓鞘的发作和发展中的重要作用，但直到最近，直到最近是否需要免疫系统才能触发该疾病。最近，使用RAG1敲除小鼠的研究表明，在没有成熟的T和B细胞的情况下，MHV感染诱导脱髓鞘，表明MHV诱导的CNS脱髓鞘不需要T和B细胞。这一发现使我们假设CNS中的MHV感染通过直接病毒杀死少突胶质细胞而破坏了髓鞘鞘。以前的观察结果证明了这一假设，即在通过亚急性脑脊髓炎的MHV感染大鼠中枢神经系统中检测到大量凋亡性少突胶质细胞。我们最近的发现也证实了MHV感染在培养的大鼠少突胶质细胞中诱导的凋亡。然而，尚不清楚MHV感染引起凋亡和破坏的凋亡和破坏的基本机制。我们提出了两个具体的目的来解决这些问题。我们将首先确定哪些病毒因素在培养的少突胶质细胞中诱导凋亡。然后，我们将阐明MHV诱导的少突胶质细胞凋亡的分子机制。这些研究将确定与MHV感染调节少突胶质细胞凋亡有关的成分和生化途径，并将提供有关CNS病毒诱导脱髓鞘疾病机制的见解。这些研究的结果将有助于开发有效的治疗干预措施，以脱髓鞘疾病（例如MS）。