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ROLES OF HOST FACTORS IN VIRAL REPLICATION COUPLED PROCESSES

宿主因素在病毒复制耦合过程中的作用

基本信息

批准号：
10561655
负责人：
Jill Ann Dembowski
金额：
$ 34.5万
依托单位：
DUQUESNE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-07 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10561655
关键词：
Address Affect Antiviral Therapy Antiviral resistance Biochemical Biological Assay Biological Models Capsid Cell Proliferation Cell physiology Cells Chromatin Chromatin Modeling Chromatin Remodeling Factor Coupled DNA DNA Damage DNA Repair DNA Repair Pathway DNA Viruses DNA biosynthesis DNA replication fork DNA-Directed DNA Polymerase Development Disease Gene Transduction Agent Genetic Genetic Recombination Genetic Transcription Goals Herpesvirus 1 Human Immunocompromised Host Infection Integration Host Factors Knowledge Late Gene Transcriptions Life Cycle Stages Lytic Maintenance Mass Spectrum Analysis Mediating Modification Molecular Outcome Pathway interactions Play Population Post-Translational Protein Processing Process Production Proliferating Cell Nuclear Antigen Protein Dynamics Proteins Proteomics Role Simplexvirus Testing Time Transcriptional Regulation Ubiquitination Viral Viral Genes Viral Genome Viral Vector Virus Virus Diseases Virus Replication chromatin modification chromatin remodeling experimental study gene therapy genome integrity genome-wide in vivo innovation insight knock-down mutant neonate oncolytic vector pathogen protein protein interaction recombinational repair recruit repaired response ubiquitin isopeptidase viral DNA

项目摘要

Herpes simplex virus is a prevalent pathogen that infects the majority of the human population. Viral DNA replication is an essential step in the virus life cycle and can be targeted by antiviral treatments. Herpesviral DNA replication is coupled to other viral processes including transcription, DNA recombination, and DNA repair. However, there are critical gaps in our current knowledge of the molecular mechanisms by which these processes are coordinated and regulated on the viral DNA. The recent development of proteomic approaches to study protein association with replication forks has enabled an in depth look at this fundamental process within cells. In addition to the viral replication machinery, select host chromatin remodeling, transcription, DNA modifying, and DNA repair factors associate with HSV-1 replication forks. Our long-term goal is to uncover how HSV-1 subverts host cellular factors to replicating viral DNA to coordinate viral DNA synthesis with DNA damage response pathways, DNA repair, and transcription in vivo. In the proposed aims, proteomic and genome-wide assays will be used to 1) investigate mechanisms that couple the viral replication machinery to cellular DNA repair pathways, 2) determine how cellular factors mediate the replication coupled switch to activate late gene transcription, and 3) dissect how replication fork associated factors regulate viral DNA topology and genome integrity. Innovative approaches will be employed to define the functions of host proteins during viral DNA replication. How viral modification of cellular factors alters cellular DNA replication and repair will also be investigated. Host proteins that are exploited during viral DNA replication can be targeted by antiviral therapies. Furthermore, insight into how viral replication is coordinated with the DNA damage response, viral chromatin, and transcription regulation will aid in the development of effective HSV-1 based gene therapy approaches and oncolytic vectors.

单纯疱疹病毒是一种感染大多数人群的流行病原体。病毒 DNA 复制是病毒生命周期中的重要步骤，可以作为抗病毒治疗的目标。疱疹病毒 DNA 复制与其他病毒过程耦合，包括转录、DNA 重组和 DNA 修复。然而，我们目前对病毒 DNA 上协调和调节这些过程的分子机制的了解还存在重大差距。最近开发的研究蛋白质与复制叉关联的蛋白质组学方法使得人们能够深入了解细胞内的这一基本过程。除了病毒复制机制外，选择宿主染色质重塑、转录、DNA 修饰和 DNA 修复因子也与 HSV-1 复制叉相关。我们的长期目标是揭示 HSV-1 如何颠覆宿主细胞因子来复制病毒 DNA，从而协调病毒 DNA 合成与 DNA 损伤反应途径、DNA 修复和体内转录。在拟议的目标中，蛋白质组学和全基因组检测将用于1）研究将病毒复制机制与细胞DNA修复途径耦合的机制，2）确定细胞因子如何介导复制耦合开关以激活晚期基因转录，以及3）剖析复制叉相关因子如何调节病毒DNA拓扑和基因组完整性。将采用创新方法来定义病毒 DNA 复制过程中宿主蛋白的功能。病毒对细胞因子的修饰如何改变细胞 DNA 复制和修复也将得到研究。抗病毒疗法可以靶向病毒 DNA 复制过程中利用的宿主蛋白。此外，深入了解病毒复制如何与 DNA 损伤反应、病毒染色质和转录调控相协调将有助于开发基于 HSV-1 的有效基因治疗方法和溶瘤载体。