Demyelinating Disease-Viral and Cellular Function

脱髓鞘疾病-病毒和细胞功能

• 批准号: 7224251
• 负责人: Xuming Zhang
• 金额: $ 18.57万
• 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 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7224251
• 关键词: Address; Animal Model; Animals; Apoptosis; Apoptotic; B-Lymphocytes; Biochemical Pathway; Caspase; Cell physiology; Central Nervous System Degenerative Diseases; Coronavirus; Data; Demyelinating Diseases; Demyelinations; Development; Disease; Encephalomyelitis; Environmental Risk Factor; Etiology; Event; Genetic; Goals; Hepatitis; Immune system; Individual; Infection; Inflammatory; Knockout Mice; Knowledge; Mature T-Lymphocyte; Modeling; Molecular; Multiple Sclerosis; Mus; Myelin Sheath; Neuraxis; Numbers; Oligodendroglia; Pathogenesis; Pathway interactions; Process; RAG1 gene; Rattus; Regulation; Research; Rodent; Role; Staging; Stimulus; Therapeutic Intervention; Viral; Viral Proteins; Virus; Virus Diseases; apoptosis inducing factor; central nervous system demyelinating disorder; human coronavirus; insight; killings

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（MS）是中枢神经系统（CNS）的炎性脱髓鞘疾病。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相关，并代表MS的候选环境触发因素。鼠冠状病毒（MHV）可在啮齿动物中诱导MS样疾病。本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。虽然大量的证据已经揭示了免疫系统在MHV诱导的脱髓鞘的发生和发展中的重要作用，但直到最近还不清楚免疫系统是否绝对需要触发该疾病。最近，使用RAG1基因敲除小鼠的研究表明，MHV感染诱导脱髓鞘在成熟的T和B细胞的情况下，表明T和B细胞都不是MHV诱导的CNS脱髓鞘所必需的。这一发现使我们假设，MHV感染中枢神经系统的结果在髓鞘的破坏，直接病毒杀死少突胶质细胞。这一假说得到了先前观察的支持，即在MHV感染的亚急性脑脊髓炎大鼠的CNS中检测到大量凋亡的少突胶质细胞。这也证实了我们最近的研究结果，MHV感染诱导培养的大鼠少突胶质细胞凋亡。然而，MHV感染引起少突胶质细胞凋亡和破坏的潜在机制尚不清楚。我们提出两个具体目标来解决这些问题。我们将首先确定哪些病毒因子诱导培养的少突胶质细胞凋亡。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MHV感染参与调节少突胶质细胞凋亡的组分和生化途径，并将为病毒诱导的CNS脱髓鞘疾病的机制提供见解。这些研究结果将有助于开发有效的脱髓鞘疾病，如MS的治疗干预。