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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：多瘤病毒会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，目前尚无针对该病毒家族的特异性抗病毒治疗或预防方法，目前我们对分子机制的了解存在一些关键空白。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。这些结果引出了我们的中心假设，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很重要。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作为促进DDR激活的新因素，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，我们建议追求三个具体目标。旨在表征 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）确定激活 DDR 的病毒 DNA 触发器。 (3) 为了阐明多瘤病毒诱导宿主基因组不稳定的分子机制，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所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和病毒肿瘤发生的新分子机制，这些发现可能会推广到其他 DNA 病毒以及我们对正常细胞过程的理解。