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Mouse Model of Progressive Multifocal Leukoencephalopathy

进行性多灶性白质脑病小鼠模型

基本信息

批准号：
8922715
负责人：
Chen Sabrina Tan
金额：
$ 26.1万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8922715
关键词：
A Mouse 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 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 Viral Proteins Virus Virus Diseases Work animal model development base brain cell effective therapy experience fetus cell immunosuppressed mortality mouse model mouse polyomavirus natalizumab nervous system disorder novel prevent protein expression public health relevance tool tumor virus pathogenesis

项目摘要

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.