Innate Defense Program against HCV

针对 HCV 的先天防御计划

• 批准号: 9242023
• 负责人: Takeshi Saito
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242023
• 关键词: 2-tyrosine; Acute Hepatitis C; Address; Antiviral Agents; Biochemical; Biochemical Genetics; Biological Models; Cells; Cessation of life; Chronic; Chronic Hepatitis C; Cirrhosis; Clinical; Collaborations; Communicable Diseases; Complementary DNA; Development; Disease; Event; Foundations; Gene Expression; Genes; Genetic Transcription; Goals; Hepatic; Hepatitis C; Hepatocyte; Human; Immune; Immune response; Immunity; In Vitro; Individual; Infection; Integration Host Factors; Interferon Type I; Interferons; Investigation; Laboratories; Liver; Liver Failure; Liver diseases; Malignant neoplasm of liver; Mediating; Molecular; Mus; Natural Immunity; Outcome; Pathogenicity; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Predisposition; Prevention strategy; Primary Prevention; Process; Protein Tyrosine Kinase; Public Health; Recruitment Activity; Regulation; Research Project Grants; Rest; Role; STAT1 gene; Serine; Signal Pathway; Signal Transduction; Signaling Molecule; TNK1 gene; Therapeutic; Transcriptional Activation; Translating; United States; Vaccines; Validation; Viral; Virus; Virus Diseases; Virus Replication; adaptive immunity; anti-hepatitis C; base; genetic approach; genome-wide; humanized mouse; in vivo; insight; mouse model; novel; permissiveness; programs; public health relevance; response; screening

 DESCRIPTION (provided by applicant): Hepatitis C Virus (HCV) efficiently establishes persistent infection, with 200 million people currently infected worldwide. In the US, chronic HCV infection accounts for 15,000 deaths via end-stage liver diseases such as liver cancer and decompensated cirrhosis. In addition, nearly 20,000 individuals are newly infected with HCV annually, thereby posing a continuous threat to public health. Thus, an effective prevention strategy remains essential to mitigating the burden of HCV. Towards this ultimate goal, furthering our understanding of host immunity against viral infection plays a critical role. Interferon stimulated genes (ISG) constitute over 300 innate immune effectors which cooperatively restrict viral infection and are critical determinants for efficient mounting of adaptive immunity. ISG expression is dynamic, occurring through differential strength and duration of interferon (IFN) signaling. However, the processes that regulate ISG expression to facilitate viral restriction are poorly defined. In search of novel host factors that stimulate ISG expression for the suppression of HCV infection, we have conducted comprehensive genome-wide cDNA screening. These studies identified the non-receptor tyrosine kinase 1 (TNK1) as a signaling molecule pivotal for enhanced ISG expression and restriction of HCV infection. Our studies indicate that TNK1 presides over a novel signaling pathway that imparts serine phosphorylation of STAT1, resulting in induction of a specific group of ISG that have potent anti-HCV activity. Therefore the proposed studies aim to investigate the hypothesis that the TNK1 pathway induces anti-HCV effectors through a unique process of STAT1 activation. We will conduct the following aims: (Aim 1) Determine the mechanism of TNK1 activation and characterize its enzymatic activity, (Aim 2) Define the signaling cascade governed by TNK1 mediated serine phosphorylation of STAT1, and (Aim 3) Determine the in vivo role of TNK1 in hepatic antiviral innate immunity. The results from this study will provide novel insights into a front line defense against viral infection and contribute to a prevention strategy against HCV infection and emerging viral diseases.

 描述（由适用提供）：丙型肝炎病毒（HCV）有效地建立了持续的感染，目前在全球范围内感染了2亿人。在美国，慢性HCV感染可通过终末期肝脏疾病（例如肝癌和肝硬化代偿症）造成15,000例死亡。此外，每年将近20,000名患有HCV新感染，从而对公共卫生构成持续威胁。这是有效的预防策略对于减轻HCV的燃烧至关重要。朝着这个最终的目标，进一步了解我们对宿主对病毒感染的免疫史的理解起着至关重要的作用。干扰素刺激的基因（ISG）构成了300多种先天免疫效应，这些效应限制了病毒感染，并且是有效安装适应性免疫史剂学的关键决定者。 ISG表达是动态的，是通过干扰素（IFN）信号传导的差异强度和持续时间发生的。但是，调节ISG表达以促进病毒限制的过程的定义很差。寻找刺激ISG的新型宿主因素 为了抑制HCV感染的表达，我们进行了全面的全基因组cDNA筛选。这些研究将非受体酪氨酸激酶1（TNK1）鉴定为信号分子关键，以增强ISG表达和HCV感染的限制。我们的研究表明，TNK1主持了一种新的信号传导途径，即无法对STAT1的丝氨酸磷酸化，从而导致具有潜在抗HCV活性的特定ISG诱导。因此，拟议的研究旨在研究TNK1途径通过独特的STAT1激活过程诱导抗HCV效应的假设。我们将执行以下目的：（目标1）确定TNK1激活的机制并表征其酶活性，（AIM 2）定义由TNK1介导的STAT1介导的丝氨酸磷酸化管辖的信号传导级联反应，（AIM 3）确定TNK1在抗肝炎抗病性抗病性含有免疫力中的体内作用。这项研究的结果将提供对针对病毒感染的前线防御的新见解，并为针对HCV感染和新兴病毒疾病的预防策略做出贡献。