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Integration of Retroviral DNA: Accessing Host Target DNA

逆转录病毒 DNA 的整合：获取宿主靶标 DNA

基本信息

批准号：
8973537
负责人：
RICHARD ALAN KATZ
金额：
$ 51.41万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-09-30 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8973537
关键词：
Adaptor Signaling Protein Address Adult Anti-Retroviral Agents Antiviral Agents Appearance Area Avian Sarcoma Viruses Binding Binding Proteins Biological Biological Models Cell physiology Cells Cellular biology Chromatin Cues DNA DNA Binding DNA Methylation DNA Sequence Development Disease Epigenetic Process Event Failure Fingers Funding Gene Expression Gene Expression Regulation Genes Goals Grant Health Histones Host Defense Mechanism Human Infection Integrase Investigation Knowledge Laboratories Lead Maintenance Malignant Neoplasms Mammalian Cell Measures Mediating Modeling Molecular Molecular Chaperones Normal Cell Nuclear Play Proteins Proviruses Recruitment Activity Repression Research Retroviral Vector Retroviridae Role Scaffolding Protein Small Interfering RNA Staging System Testing Tissues Viral Virus Diseases Virus-Cell Membrane Interaction Work adapter protein base cancer cell cohesin gene repression genome-wide histone modification human disease innovation insight novel prevent prototype response screening success viral DNA virology virus host interaction

项目摘要

DESCRIPTION (provided by applicant): This competitive renewal application continues to focus on the early stages of retroviral replication. The overarching goal of this application is to uncover critical cell-virus interactions that determine the success or failure of retroviral gene expression in human cells, as modulated by epigenetic silencing. It was established decades ago that the prototype avian sarcoma virus (ASV) DNA provirus is subject to epigenetic silencing in mammalian cells, and this system will continue to be studied as a model. The applicants have discovered that epigenetic silencing of ASV can be mediated by the rapid engagement of an antiviral host adaptor protein, Daxx, which recruits the cellular epigenetic silencing machinery. Furthermore, through development and implementation of an innovative, robust, and comprehensive siRNA-based screen, a number of novel and expected human host cell factors that play a role in this response were identified. These findings have opened up the exciting new areas of investigation to be pursued in this competing renewal. In Aim 1, the molecular mechanisms that govern Daxx function as an antiviral factor will be determined. Results of these studies will provide valuable insight into general intrinsic host defense mechanisms. In Aim 2 mechanistic details for the function of several novel factors identified by siRNA screening will be studied, with a focus on those likely to engage viral DNA sequences. The hypotheses that specific viral DNA binding factors either participate in nucleation of silencing factors or act as a transcriptional barrier, will be tested. Aim 3 will exploit new comprehensive and systematic approaches to distinguish the physical and functional epigenetic features of silent proviruses that are established soon after infection (initiation) and after long-term passage (maintenance). Specific hypotheses concerning the roles of antiviral factors, and the interplay of proviral and cellular chromatin, in silencing will be considered. Epigenetic mechanisms have an essential role in the regulation of gene expression during development, in differentiated adult tissues, and in human disease, including cancer. Consequently, results from the proposed research will be highly relevant to virology, as well as the cellular biology of normal and cancer cells.

描述（由申请人提供）：该竞争性续展申请继续关注逆转录病毒复制的早期阶段。该应用的首要目标是揭示关键的细胞病毒相互作用，这些相互作用决定了人类细胞中逆转录病毒基因表达的成功或失败，并受到表观遗传沉默的调节。几十年前就已经确定，原型禽肉瘤病毒 (ASV) DNA 原病毒在哺乳动物细胞中会受到表观遗传沉默，并且该系统将作为模型继续进行研究。申请人发现ASV的表观遗传沉默可以通过抗病毒宿主衔接蛋白Daxx的快速接合来介导，Daxx招募细胞表观遗传沉默机制。此外，通过开发和实施创新、稳健和全面的基于 siRNA 的筛选，确定了许多在这种反应中发挥作用的新型和预期的人类宿主细胞因子。这些发现开辟了这一竞争性更新中令人兴奋的新研究领域。在目标 1 中，将确定控制 Daxx 作为抗病毒因子发挥作用的分子机制。这些研究的结果将为了解一般内在宿主防御机制提供有价值的见解。在目标 2 中，将研究通过 siRNA 筛选确定的几种新因子的功能机制细节，重点关注那些可能与病毒 DNA 序列结合的因子。特定病毒 DNA 结合因子参与沉默因子的成核或充当转录屏障的假设将得到测试。目标 3 将利用新的全面和系统的方法来区分沉默原病毒的物理和功能表观遗传特征，这些特征是在感染（启动）后不久和长期传代（维持）后建立的。将考虑有关抗病毒因子在沉默中的作用以及原病毒和细胞染色质的相互作用的具体假设。表观遗传机制在发育过程中、分化的成体组织以及包括癌症在内的人类疾病中的基因表达调节中发挥着重要作用。因此，拟议研究的结果将与病毒学以及正常细胞和癌细胞的细胞生物学高度相关。