Reciprocal Interaction of JCV and Host Regulators

JCV 和主机调节器的相互作用

• 批准号: 7798567
• 负责人: Kamel Khalili
• 金额: $ 29.74万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7798567
• 关键词: Affect; Apoptosis; Astrocytes; Autopsy; Brain; Brain Pathology; Cell Culture Techniques; Cell Cycle; Cell Cycle Regulation; Cell Death; Cell Nucleus; Cell Proliferation; Cells; Central Nervous System Diseases; Clinical; Collaborations; Cyclins; DNA Repair; DNA biosynthesis; Demyelinations; Development; Double Strand Break Repair; Early Gene Transcriptions; Evaluation; Event; Foundations; G22P1 gene; Gene Expression; Gene Expression Regulation; Genes; Genetic Recombination; Genome; Genome Stability; Hand; Homeostasis; IGF-1 Signaling Pathway; Immunocompromised Host; In Vitro; Infection; JC Virus; Late Gene Transcriptions; Light; Lytic Phase; Mediating; Molecular; Molecular Biology; Myelin Sheath; Neuraxis; Neuroglia; Nonhomologous DNA End Joining; Oligodendroglia; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patients; Phase; Process; Production; Program Research Project Grants; Progressive Multifocal Leukoencephalopathy; Proteins; Research Project Grants; Role; Sampling; Staging; Staining method; Stains; Structural Protein; TP53 gene; Therapeutic Intervention; Tissue Sample; Tropism; Tumor Suppressor Proteins; Viral; Viral Genes; Viral Proteins; Viral Tumor Antigens; Virus; Virus Diseases; base; brain tissue; cell type; central nervous system demyelinating disorder; gene interaction; genetic regulatory protein; homologous recombination; protein expression; repaired; sialosyl-T antigen; tissue tropism; viral DNA; white matter

The human polyomavirus, JCV, is the etiologic agent of Progressive Multifocal Leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system (CNS) that usually affects immunosuppressed patients. JCV has an unusually narrow tissue tropism which restricts its productive replication to oligodendrocytes, a subclass of glial cells in the CNS which are responsible for production of the myelin sheath. Earlier studies by us and others have indicated that the cell type-specific tropism of JCV to glial cells is determined at the level of viral early gene transcription, which is responsible for the production of T-antigen. In collaboration with host regulatory proteins, T-antigen orchestrates subsequent events during the viral lytic cycle including viral DNA replication and late gene transcription and leads to the destruction of oligodendrocytes and demyelination of the brain. Histological analysis of PML brains has revealed that in addition to demyelination of white matter, a number of abnormalities are observed in both surviving oligodendrocytes and the other subclass of glial cells, astrocytes, suggesting dyregulation of pathways responsible for host cell homeostasis including control of the cell cycle and DNA repair. In support of this notion, results from immunohistochemical staining of clinical samples revealed the presence of double-strand breaks, indicative of dysfunctionality of DNA repair, an unusual expression of proteins which are in control of cellular proliferation, and apoptosis. Accordingly, results from in vitro cell culture infection revealed that the JCV early protein, T-antigen, and the viral non-structural protein, Agnoprotein, by dysregulating the level of expression and activities of factors involved in cell cycle control and DNA repair may affect a process that leads to the development of some of the pathological features that are seen in oligodendrocytes and astrocytes of PML. In this research project we aim to: (i) investigate the effect of JCV early protein on process involved in genomic stability at the early stage of viral infection by analyzing its interaction with IRS-1, p53, and Rad51, three critical proteins that, by communicating with T-antigen, can influence the process of homologous recombination; (ii) determine the molecular mechanisms by which the JCV late protein, Agnoprotein, through its association with p53 and Ku70 dysregulates non-homologous end joining during the course of infection. Such comprehensive studies of viral -host interaction at the molecular level should enable us to understand the molecular pathogenesis of JCV-CNS disorders and provide us with pivotal information for therapeutic intervention.

人类多瘤病毒JCV是进行性多灶性白细胞气息（PML）的病因学药物，这是一种致命的中枢神经系统（CNS）致命的脱髓鞘疾病，通常会影响免疫抑制的患者。 JCV具有异常狭窄的组织对流，该组织将其生产性复制限制为少突胶质细胞，少突胶质细胞是中枢神经系统中胶质细胞的子类，该子类负责髓鞘的产生。我们和其他人的早期研究表明，在病毒早期基因转录水平上确定了JCV对神经胶质细胞的细胞类型特异性，这是负责T-抗原的产生的。与宿主调节蛋白合作，T-抗原在病毒裂解周期中策划了随后的事件，包括病毒DNA复制和晚期基因转录，并​​导致破坏 大脑的少突胶质细胞和脱髓鞘。 PML大脑的组织学分析表明，除了白质的脱髓现外，在存活的少突胶质细胞和其他胶质细胞的其他子类中都观察到许多异常，星形胶质细胞，表明负责造成宿主细胞体内稳态的途径，包括控制细胞周期和DNA修复。为了支持这一概念，临床样品的免疫组织化学染色引起的结果表明，双链断裂的存在，表明DNA修复功能障碍，这是蛋白质的异常表达 细胞增殖和凋亡。因此，通过体外细胞培养感染的结果表明，JCV早期蛋白，T-抗原和病毒非结构蛋白Agnoprotoin，通过失调的调节，与细胞周期控制和DNA修复有关的因素的表达水平和活性失调，可能会影响一项导致在OligodendRocytess和pherlocytes中的病理特征的过程，这些过程可能会导致某些病理特征的发展。在该研究项目中，我们的目的是：（i）研究JCV早期蛋白对病毒感染早期涉及基因组稳定性的过程的影响，通过分析其与IRS-1，p53和Rad51的相互作用，三种关键蛋白，通过与T-抗原进行沟通，可以影响同源性重组的过程； （ii）确定JCV晚期蛋白与p53和KU70通过其关联的分子机制，在感染过程中与非同源末端连接失调。对分子水平的病毒 - 固定相互作用的全面研究应该使我们能够理解JCV -CNS疾病的分子发病机理，并为我们提供有关治疗干预的关键信息。