Mouse Model of Progressive Multifocal Leukoencephalopathy

进行性多灶性白质脑病小鼠模型

• 批准号: 9036470
• 负责人: Chen Sabrina Tan
• 金额: $ 21.75万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036470
• 关键词: Acquired Immunodeficiency Syndrome; Amino Acids; Animal Model; Animals; Anti-Retroviral Agents; Autoimmune Diseases; Biology; Brain; Capsid; Cells; Central Nervous System Infections; Central Nervous System Viral Diseases; Complication; Cytolysis; DNA-Directed DNA Polymerase; Data; Demyelinations; Development; Disease; Event; General Population; Goals; HIV; Health; Hematopoietic; Histology; Immune; Immune response; Immunocompromised Host; Immunologics; In Vitro; Individual; JC Virus; Knowledge; Lead; Life; Lytic Phase; Malignant Neoplasms; Mammary gland; Mission; Modeling; Molecular Virology; Monoclonal Antibodies; Morbidity - disease rate; Multiple Sclerosis; Mus; Myelin; NIH 3T3 Cells; Neuraxis; Neuroglia; Oligodendroglia; Outcome Study; Pathogenesis; Pathogenicity; Patients; Polyomavirus; Prevention; Preventive; Production; Progressive Multifocal Leukoencephalopathy; Public Health; Rattus; Regulation; Research; Research Personnel; Serum; Testing; Therapeutic; Therapeutic Intervention; Urine; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; animal model development; base; brain cell; effective therapy; experience; fetus cell; humanized mouse; immunosuppressed; mortality; mouse model; mouse polyomavirus; natalizumab; nervous system disorder; novel; novel therapeutics; prevent; protein expression; tool; tumor; virus pathogenesis

 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.

 描述(申请人提供)：进行性多灶性白质脑病(PML)，由JC病毒(JCV)重新激活引起，仍然是一种威胁生命的定义艾滋病的中枢神经系统感染。此外，用抗癌或自身免疫性疾病的单抗治疗的HIV阴性患者也会发生PML。虽然正常人尿液中的JCV无症状，但PML患者脑内JCV的重新激活会造成严重的髓鞘破坏。因此，阻止JC病毒在大脑中的复制可以防止进展为PML。然而，对PML发病前中枢神经系统发生的病毒学和免疫学事件的了解有限，缺乏动物模型阻碍了对PML发病机制的更好理解。我们的总体目标是生成PML的鼠标模型。我们的中心假设是，一种新型嵌合的小鼠-JC多瘤病毒，含有小鼠的复制机制和神经病原型JCV衣壳，将导致小鼠少突胶质细胞的生产性和裂解性感染，并概括了小鼠PML的发病机制。其基本原理是基于以前对从PML患者脑脊液中分离的小鼠多瘤病毒和JCV毒株的研究，表明由于VP1衣壳的变化而改变了致病性，以及我们的初步数据证明了一种新的嵌合小鼠-JC多瘤病毒rMPyV-JCVMad的创建。为了进一步了解导致JCV重新激活的免疫事件和PML的发展，迫切需要PML的小鼠模型。这种小动物模型将对设计HIV+和其他免疫抑制患者的PML预防和治疗策略至关重要。基于我们强大的初步数据，我们将通过追求以下特定目标来验证这一假说：目的1.体外鉴定rMPyV-JCVMad嵌合病毒。目的2.建立PML小鼠模型。建议的研究借鉴了我们在分子病毒学、组织学和先前的小鼠研究方面的丰富经验。包括新型嵌合小鼠-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。这项拟议的工作将建立首个PML动物模型，这将扩大我们对中枢神经系统JCV发病机制的理解，并为治疗干预提供新的靶点。