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The Role of Viral Receptors in JCV Reactivation and Progression to PML in AIDS

病毒受体在 AIDS 中 JCV 重新激活和进展为 PML 中的作用

基本信息

批准号：
8016654
负责人：
Melissa Maginnis
金额：
$ 5.3万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8016654
关键词：
Acquired Immunodeficiency Syndrome Asparagine Binding Binding Sites Biochemical Biological Biological Assay Biology Calcium Calmodulin Cell physiology Cell surface Cells Complex Confocal Microscopy Demyelinating Diseases Development Disease Disease susceptibility Epithelium Genetic Genetic Transcription Glycoproteins Human Immunocompromised Host Individual Infection Invaded JC Virus Kidney Life Link Measures Mediating Melissa Molecular Mutate Neuraxis Neuroglia Neurons Oligodendroglia PDZ protein Pathogenesis Pathway interactions Patients Phosphorylation Phosphotransferases Play Population Progressive Multifocal Leukoencephalopathy Proteins Receptor Cell Receptor Signaling Research Research Personnel Role Serotonin Sialic Acids Signal Pathway Signal Transduction Signaling Molecule Site Site-Directed Mutagenesis Tertiary Protein Structure Testing Tropism Viral Viral Physiology Virus Virus Diseases Virus Receptors base combinatorial extracellular glycosylation inhibitor/antagonist insight mutant novel pathogen protein function public health relevance receptor receptor internalization research study response serotonin 5 receptor transcription factor

项目摘要

DESCRIPTION (provided by applicant): Virus receptors are important host-cell determinants that govern viral tropism, spread, and disease pathogenesis. Understanding the molecular interactions between viruses and their cognate receptors provides significant insight into virus biology and disease. The human polyomavirus JC virus (JCV) is an important pathogen that infects the majority of the human population. While initial infection with JCV proves relatively asymptomatic, the virus establishes a persistent, life-long infection in the kidney. In immunocompromised individuals JCV can become reactivated and spread to the central nervous system (CMS). In the CMS, JCV infects oligodendrocytes, glial cells that provide support for neurons. JCV infection causes cytolytic destruction of oligodendrocytes leading to the fatal disease, Progressive Multifocal Leukoencephalopathy (PML). Approximately 5-8% of individuals with AIDS develop PML. The basic mechanisms by which JCV engages host-cell receptors and elicits signaling pathways to initiate an infectious cycle remains poorly understood. A combinatorial approach utilizing genetic, biochemical, and cell biological strategies will help to elucidate the mechanisms by which JCV-receptor interactions leads to infection and PML. Three integrated specific aims are proposed. The first aim will determine the molecular mechanisms by which JCV engages the serotonin receptor 5-HT2AR to mediate viral attachment and entry. The second aim will define the signaling pathways activated in response to JCV infection, and explore the role of 5-HT2AR in JCV-induced signaling pathways. The third aim will investigate the role of PDZ-domain proteins in JCV infection. Public Health Relevance: Taken together, these studies will enhance our understanding of JCV-host-cell tropism and the molecular mechanisms underlying the pathogenesis of PML.

描述（由申请方提供）：病毒受体是重要的宿主细胞决定因子，控制病毒的嗜性、传播和疾病发病机制。了解病毒与其同源受体之间的分子相互作用为病毒生物学和疾病提供了重要的见解。人类多瘤病毒JC病毒（JCV）是感染大多数人类的重要病原体。虽然JCV的初始感染证明相对无症状，但该病毒在肾脏中建立了持续的终身感染。在免疫功能低下的个体中，JCV可以被重新激活并扩散到中枢神经系统（CMS）。在CMS中，JCV感染少突胶质细胞，为神经元提供支持的神经胶质细胞。JCV感染引起少突胶质细胞的细胞溶解性破坏，导致致命性疾病，进行性多灶性白质脑病（PML）。大约5-8%的艾滋病患者会发展为PML。JCV与宿主细胞受体和elevant信号通路结合以启动感染周期的基本机制仍然知之甚少。利用遗传，生物化学和细胞生物学策略的组合方法将有助于阐明JCV-受体相互作用导致感染和PML的机制。提出了三个综合的具体目标。第一个目标将确定JCV与5-羟色胺受体5-HT 2AR结合以介导病毒附着和进入的分子机制。第二个目的是确定JCV感染后激活的信号通路，并探讨5-HT 2AR在JCV诱导的信号通路中的作用。第三个目标是研究PDZ结构域蛋白在JCV感染中的作用。公共卫生相关性：总之，这些研究将加强我们对JCV-宿主细胞嗜性和PML发病机制的分子机制的理解。