Intersection of polyomavirus infection and host cellular responses

多瘤病毒感染与宿主细胞反应的交叉点

• 批准号: 9077878
• 负责人: Sunnie R Thompson
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-11 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9077878
• 关键词: Affect; BK Virus; Biological Assay; Cancer Etiology; Cell Culture Techniques; Cell Cycle Arrest; Cell physiology; Cells; Chromosomes; Complex; Coupled; DNA Damage; DNA Replication Damage; DNA Structure; DNA Viruses; DNA biosynthesis; DNA replication fork; Data; Disease; Epithelial Cells; Equilibrium; Family; Genome; Genome Stability; Genomic DNA; Genomic Instability; Goals; Human; Immunocompromised Host; Individual; Infection; Knowledge; Large T Antigen; Lead; Life; Link; Longitudinal Studies; M cell; Maintenance; Malignant Neoplasms; Mismatch Repair; Mitotic; Modeling; Molecular; Nuclear; Pathway interactions; Play; Polyomavirus; Polyomavirus Infections; Population; Proteins; Proteomics; Proximal Kidney Tubules; Research; Role; Satellite Viruses; Side; Signal Transduction; Signaling Molecule; Source; Stress; System; Testing; Text; Viral; Viral Genome; Viral Oncogene; Viral Tumor Antigens; Virus; Virus Diseases; Virus Replication; genome integrity; human disease; novel; novel therapeutics; prevent; prophylactic; public health relevance; response; tumorigenesis; viral DNA

 DESCRIPTION (provided by applicant): Polyomaviruses cause a variety of severe human diseases particularly in immunocompromised individuals. No specific anti-viral treatments or prophylactic approaches exist to target this family of viruses. There are several critical gaps in our current knowledge of the molecular mechanism of viral replication and tumorigenesis. Our long-term goals are to identify how these viruses subvert normal host cellular processes to facilitate viral replication, and how these interactions may result in oncogenesis. Our previous studies revealed an intricate balanced relationship between viral replication and virus-induced host genomic instability. These results lead to our central hypothesis that an activated cellular DNA damage response (DDR) is important for facilitating viral replication and maintaining host genome stability during polyomavirus infection. Towards this hypothesis, we have identified host mismatch repair system and replicating viral DNA as novel factors contributing to DDR activation. We have also discovered that the ability of polyomavirus to cause host genomic DNA damage is linked to its ability to replicate viral DNA. Guided by strong preliminary data, we propose to pursue three Specific Aims to characterize DDR activation mechanism and how the DDR ties together viral replication and host genomic stability: (1) To define the role of host mismatch repair proteins in polyomavirus replication and polyomavirus-induced DDR activation. (2) To determine the viral DNA triggers that activate the DDR upon polyomavirus infection. (3) To elucidate the molecular mechanism by which polyomavirus induces host genome instability. Collectively, our proposed research will broadly impact the field by characterizing the essential roles that the DDR plays in promoting viral replication and maintaining host genome stability. These studies will have the potential to uncover novel molecular mechanisms underlying polyomavirus replication as well as viral oncogenesis. These findings may be extrapolated to other DNA viruses and to our understanding of normal cellular processes.

 描述（由申请方提供）：多瘤病毒引起多种严重的人类疾病，特别是在免疫功能低下的个体中。目前还没有针对该病毒家族的特异性抗病毒治疗或预防方法。在我们目前对病毒复制和肿瘤发生的分子机制的认识中存在几个关键的空白。我们的长期目标是确定这些病毒如何破坏正常宿主细胞过程以促进病毒复制，以及这些相互作用如何导致肿瘤发生。我们以前的研究揭示了病毒复制和病毒诱导的宿主基因组不稳定性之间复杂的平衡关系。这些结果导致了我们的中心假设，即激活的细胞DNA损伤反应（DDR）对于促进病毒复制和维持多瘤病毒感染期间宿主基因组的稳定性是重要的。针对这一假设，我们已经确定了宿主错配修复系统和复制病毒DNA作为新的因素，有助于DDR激活。我们还发现，多瘤病毒引起宿主基因组DNA损伤的能力与其复制病毒DNA的能力有关。在强有力的初步数据的指导下，我们提出了三个具体目标来表征DDR激活机制以及DDR如何将病毒复制和宿主基因组稳定性联系在一起：（1）确定宿主错配修复蛋白在多瘤病毒复制和多瘤病毒诱导的DDR激活中的作用。(2)确定多瘤病毒感染后激活DDR的病毒DNA触发因子。(3)阐明多瘤病毒诱导宿主基因组不稳定性的分子机制。总的来说，我们提出的研究将通过表征DDR在促进病毒复制和维持宿主基因组稳定性方面发挥的重要作用来广泛影响该领域。这些研究将有可能揭示多瘤病毒复制以及病毒肿瘤发生的新分子机制。这些发现可以外推到其他DNA病毒和我们对正常细胞过程的理解。