Mouse Model of Progressive Multifocal Leukoencephalopathy

 描述（由申请方提供）：由JC病毒（JCV）再活化引起的进行性多灶性白质脑病（PML）仍然是一种危及生命的中枢神经系统AIDS定义感染。此外，PML也发生在接受癌症或自身免疫性疾病单克隆抗体治疗的HIV阴性患者中。虽然健康个体尿液中JCV的脱落是无症状的，但PML患者脑中JCV的重新激活会导致髓鞘破坏造成严重损害。因此，停止JC病毒在大脑中的复制可以防止进展为PML。然而，对PML发作前CNS中发生的病毒学和免疫学事件的了解是有限的;由于缺乏动物模型，阻碍了对PML发病机制的更好理解。我们的总体目标是产生PML的小鼠模型。我们的中心假设是，一种新的嵌合鼠-JC多瘤病毒，窝藏鼠复制机制和神经致病性型JCV衣壳将导致生产性和溶解性感染的小鼠少突胶质细胞，并重演的PML在小鼠中的发病机制。其原理是基于先前对从PML患者CSF中分离的鼠多瘤病毒和JCV毒株的研究，表明由于VP 1衣壳的变化而改变了致病性，以及我们的初步数据证明了新型嵌合鼠-JC多瘤病毒rMPyV-JCVMad的产生。急需一种PML小鼠模型来进一步了解导致JCV再激活和PML发展的免疫事件。这种小动物模型将是至关重要的预防和治疗策略的PML在HIV+和其他免疫抑制患者。基于我们强有力的初步数据，我们将通过追求以下具体目标来验证这一假设：目标1。体外表征rMPyV-JCVMad嵌合病毒。目标二。建立PML小鼠模型。拟议的研究借鉴了我们在分子病毒学、组织学和先前小鼠研究方面的丰富经验。包括新型嵌合鼠JC多瘤病毒在内的新工具的开发也将对其他研究人员有用，并将为发现预防和治疗PML的新靶点铺平道路。这项拟议的工作将产生第一个PML动物模型，这将扩大我们对CNS中JCV发病机制的理解，并揭示治疗干预的新靶点。

 DESCRIPTION (provided by applicant): Progressive Multifocal Leukoencephalopathy (PML), caused by the reactivation of JC virus (JCV), remains a life-threatening AIDS-defining infection of the central nervous system. In addition, PML also occurs in HIV- negative patients treated with monoclonal antibodies for cancer or autoimmune diseases. Although the shedding of JCV in the urine of healthy individual is asymptomatic, the reactivation of JCV in the brain of PML patients causes severe damages from destruction of myelin. Therefore, halting JC viral replication in the brain can prevent progression to PML. However, knowledge of the virologic and immunologic events occurring in the CNS prior to onset of PML is limited; better understanding of PML pathogenesis is hampered by the lack of an animal model. Our overall goal is to generate a mouse model of PML. Our central hypothesis is that a novel chimeric murine-JC polyomavirus, harboring the murine replication machinery and the neuropathogenic type JCV capsid will cause productive and lytic infection of mouse oligodendrocytes, and recapitulate the pathogenesis of PML in mice. The rationale is based on previous studies of murine polyomavirus and JCV strains isolated from the CSF of PML patients, indicating altered pathogenicity due to changes in the VP1 capsid, as well as our preliminary data demonstrating the creation of a novel chimeric murine-JC polyomavirus, rMPyV-JCVMad. A mouse model of PML is urgently needed to further our understanding of immune events leading to JCV reactivation and the development of PML. Such small animal model will be crucial in devising preventive and therapeutic strategies for PML in HIV+ and other immunosuppressed patients. Based on our strong preliminary data, we will test this hypothesis by pursuing these specific aims: Aim 1. Characterize rMPyV-JCVMad chimeric virus in vitro. Aim 2. Develop a mouse model of PML. The proposed studies draw upon our extensive experiences in molecular virology, histology, and prior mouse studies. The development of new tools, including the novel chimeric murine-JC polyomavirus will also be useful to other researchers and will pave the way for the discovery of new targets for prevention and treatment of PML. This proposed work will produce the first animal model of PML, which will expand our understanding of JCV pathogenesis in the CNS, and reveal new targets for therapeutic interventions.