Host-pathogen interactions in hepatitis C virus replication

丙型肝炎病毒复制中宿主与病原体的相互作用

• 批准号: 8470632
• 负责人: Shelton Stewart Bradrick
• 金额: $ 11.07万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8470632
• 关键词: 3' Untranslated Regions; 5' Untranslated Regions; Academic Medical Centers; Antiviral Therapy; Award; Biochemical Genetics; Biology; Blood; Cell Culture Techniques; Cells; Cellular Stress; Cellular Stress Response; Cessation of life; Chronic; Complex; Comprehension; Data; Development; Elements; Endoplasmic Reticulum; Ensure; Environment; Event; Exhibits; Future; Gene Expression; Genetic Translation; Genome; Genomics; Genotype; Geographic Distribution; Goals; Health; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Human Virus; In Vitro; Individual; Infection; Interferons; Internal Ribosome Entry Site; Investigation; Knowledge; Life; Life Cycle Stages; Liver; Liver diseases; Mediating; Mentors; Messenger RNA; Methods; Modality; Molecular; Morbidity - disease rate; North America; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Persons; Phase; Polyproteins; Polyribosomes; Population; Principal Investigator; Protein Biosynthesis; Proteins; RNA; RNA Virus Infections; RNA Viruses; RNA chemical synthesis; RNA-Binding Proteins; RNA-Protein Interaction; Recruitment Activity; Research; Research Project Grants; Research Proposals; Ribavirin; Ribonucleoproteins; Ribosomes; Role; Translations; Viral; Viral Genes; Viral Proteins; Virus; Virus Diseases; Virus Replication; base; career; design; global health; insight; interest; liver infection; liver transplantation; mortality; novel; novel strategies; pathogen; programs; protein expression; research study; response; virus host interaction

DESCRIPTION (provided by applicant): In this application for a mentored career award, the applicant seeks to expand the scope of his research efforts at Duke University Medical Center by applying novel approaches to investigation of hepatitis C virus (HCV) biology. It is anticipated that the proposed phase of mentored research will firmly establish the applicant's scientific independence and allow him to successfully compete for R01 research grant support in the future. The overall research objective of this career application is to identify and characterize molecular determinants of HCV replication that ultimately contribute to liver pathogenesis. HCV is a signficant [sic] human pathogen that chronically infects liver hepatocytes, often resulting in life-threatening complications. Three specific aims comprise the research proposal. I) The RNA genome of HCV has evolved unique functional elements to achieve replication within infected cells. Of particular interest, an internal ribosome entry site (IRES) located within the viral 5' untranslated region (UTR) recruits cellular ribosomes to mediate synthesis of viral proteins required for replication. We have discovered that the HCV IRES is dynamically regulated under conditions of cellular stress. Experiments proposed in specific aim I are designed to mechanistically decipher the role of cell stress in HCV protein synthesis and replication. II) RNA-protein interactions between the HCV genome and specific cellular factors are believed to facilitate virus replication, with direct implications for pathogenesis. We have identified multiple proteins that interact with the 3' UTR of HCV. Probing the functionality of these interactions in the context of HCV-infected cells is the subject of the second specific aim. Ill) The re-programming of cellular mRNA translation is a common theme in RNA virus infection, but knowledge of this phenomenon with regard to HCV is lacking. In specific aim III, we propose to employ a global approach to define mRNAs that are translationally regulated in response to HCV infection. These experiments will identify novel host pathways that are manipulated by HCV to benefit viral replication and persistence. Together, the experiments proposed by the applicant are expected to uncover novel molecular aspects of HCV infection that may be targeted therapeutically. PUBLIC HEALTH RELEVANCE: The hepatitis C virus (HCV) is a prominent human pathogen that chronically replicates within the liver of infected persons, often resulting in severe complications and death. The overall goal of the research proposed in this career award application is to understand, at the molecular level, how HCV manipulates host cells in order to ensure its own propagation.

描述（由申请人提供）： 在这项指导职业奖的申请中，申请人试图通过应用新颖的方法来调查丙型肝炎病毒（HCV）生物学，以扩大他在杜克大学医学中心的研究范围。预计拟议的指导研究阶段将牢固建立申请人的科学独立性，并允许他成功地争夺R01研究赠款的支持。该职业应用的总体研究目标是识别和表征HCV复制的分子决定因素，最终导致肝脏发病机理。 HCV是一种显着的人类病原体，长期感染肝细胞，通常导致危及生命的并发症。三个特定目标包括研究建议。 i）HCV的RNA基因组已经发展出独特的功能元件，以在感染细胞内复制。特别令人感兴趣的是，位于病毒5'未翻译区域（UTR）内的内部核糖体进入位点（IRE）募集细胞核糖体，以介导复制所需的病毒蛋白的合成。我们发现，在细胞应激条件下，HCV IRE受动态调节。在特定目的I中提出的实验旨在将细胞应激在HCV蛋白合成和复制中的作用进行机械学破解。 ii）HCV基因组和特定细胞因子之间的RNA-蛋白相互作用被认为可以促进病毒复制，对发病机理有直接影响。我们已经确定了与HCV的3'UTR相互作用的多种蛋白质。在HCV感染细胞的背景下探测这些相互作用的功能是第二个特定目的的主题。生病）重新编程细胞mRNA翻译是RNA病毒感染中的一个常见主题，但是缺乏对HCV现象的了解。在特定的目标III中，我们建议采用一种全球方法来定义对HCV感染响应的翻译调节的mRNA。这些实验将确定由HCV操纵的新型宿主途径，以使病毒复制和持久性受益。总之，申请人提出的实验预计将发现可能以治疗方法靶向的HCV感染的新型分子方面。 公共卫生相关性：丙型肝炎病毒（HCV）是一种突出的人类病原体，在感染者的肝脏内长期复制，通常会导致严重的并发症和死亡。该职业奖项申请中提出的研究的总体目标是在分子层面了解HCV如何操纵宿主细胞以确保其自身传播。