Cytomegalovirus and Nuclear Tumor Suppressors

巨细胞病毒和核肿瘤抑制因子

• 批准号: 8090262
• 负责人: TIMOTHY F KOWALIK
• 金额: $ 39.06万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090262
• 关键词: ATM gene; ATM wt Allele; Affect; Binding; Biological Assay; CDC25A gene; CHEK2 gene; Cell Nucleus; Cells; Cytomegalovirus; Cytomegalovirus Infections; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; DNA Replication Damage; DNA Viruses; DNA biosynthesis; Dominant-Negative Mutation; Event; Fibroblasts; Future; Gene Expression; Genetic Recombination; Genomics; Goals; Immune response; Infection; NBS1 gene; Nonhomologous DNA End Joining; Nuclear; Pathway interactions; Phosphotransferases; Play; Reactive Oxygen Species; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Stress; Tumor Suppressor Proteins; Virus; Virus Diseases; Virus Replication; Work; ataxia telangiectasia mutated protein; biological adaptation to stress; gene function; homologous recombination; inhibitor/antagonist; response

DESCRIPTION (provided by applicant): My long-term goal is to understand the relationship between regulatory functions in the nucleus and the replication of human cytomegalovirus (HCMV) and other DNA viruses. This project examines the host response to HCMV infection relating to "genomic stress", in particular the cellular DNA damage response, and how this response affects HCMV replication. It is known that HCMV infected cells result in a p53 response, whose function is apparently thwarted by IE2 binding. However, the event(s) that leads to the initial host attempt to activate p53 are not understood. We find that the kinase encoded by the ataxia telangiectasia mutated (Atm) gene is activated and phosphorylates p53 during infection. Atm is usually activated in response to genomic stresses such as DNA damage. Once activated, Atm signals proliferation checkpoints and stimulates DNA repair/recombination functions. Given these profound effects associated with Atm signaling, I hypothesize that the event(s) responsible for Atm activation and subsequent signaling affect the ability of HCMV to replicate. Contrary to the role activated Atm normally plays in blocking DNA synthesis, our preliminary results suggest that Atm is required for optimal HCMV replication. Thus it appears that HCMV activates a nuclear stress response in cells and then uses it to facilitate virus replication. In this application, I propose to determine how Atm is activated and its role in modulating HCMV replication, and to identify the event(s) responsible for Atm activation and determine their role in HCMV replication. A result of this research will be the identification of new potential targets for the treatment of cytomegalovirus infections. Future work will determine whether other viruses active and require the same pathways for replication and possibly expand the list of viruses that might be inhibited by targeting these pathways.

描述(申请人提供)：我的长期目标是了解细胞核调节功能与人类巨细胞病毒(HCMV)和其他DNA病毒复制之间的关系。本项目研究与“基因组应激”有关的宿主对巨细胞病毒感染的反应，特别是细胞DNA损伤反应，以及这种反应如何影响巨细胞病毒的复制。已知HCMV感染细胞可引起P53反应，其功能明显受IE2结合的抑制。然而，导致宿主最初试图激活p53的事件(S)尚不清楚。我们发现，由共济失调毛细血管扩张突变(ATM)基因编码的激酶在感染过程中被激活并磷酸化P53。ATM通常被激活，以响应基因组压力，如DNA损伤。一旦被激活，ATM就会向增殖检查点发出信号，并刺激DNA修复/重组功能。鉴于这些与ATM信令相关的深刻影响，我假设负责ATM激活和后续信令的事件(S)会影响人巨细胞病毒的复制能力。与激活的ATM通常在阻止DNA合成方面所起的作用相反，我们的初步结果表明，ATM是优化HCMV复制所必需的。因此，似乎HCMV激活了细胞中的核应激反应，然后利用它来促进病毒复制。在这个应用中，我建议确定ATM是如何激活的，以及它在调节巨细胞病毒复制中的作用，并确定负责ATM激活的事件(S)，并确定它们在巨细胞病毒复制中的作用。 这项研究的结果将是确定治疗巨细胞病毒感染的新的潜在靶点。未来的工作将确定其他病毒是否活跃，是否需要相同的复制路径，并可能扩大通过靶向这些路径可能被抑制的病毒列表。