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（由申请人提供）：丙型肝炎病毒（HCV）有效地造成持续感染，目前全球有 2 亿人感染，在美国，慢性 HCV 感染导致 15,000 人因肝癌和失代偿性肝硬化等终末期肝病死亡。此外，每年有近20,000人新感染HCV，对公众健康构成持续威胁，因此，有效的预防策略仍然至关重要。为了实现这一最终目标，进一步了解宿主对病毒感染的免疫力发挥着关键作用，干扰素刺激基因 (ISG) 构成了 300 多个先天免疫效应子，它们协同限制病毒感染，是有效安装病毒的关键决定因素。 ISG 表达是动态的，通过干扰素 (IFN) 信号强度和持续时间的差异而发生。然而，调节 ISG 表达以促进病毒限制的过程尚不清楚。 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，这些研究确定了非受体酪氨酸激酶 1 (TNK1) 作为增强 ISG 表达和限制 HCV 感染的关键信号分子。 TNK1 负责一种新的信号通路，该信号通路赋予 STAT1 丝氨酸磷酸化，从而诱导具有有效抗 HCV 活性的特定 ISG 组。因此，拟议的研究旨在调查以下假设： TNK1 通路通过 STAT1 激活的独特过程诱导抗 HCV 效应子我们将实现以下目标：（目标 1）确定 TNK1 激活机制并表征其酶活性，（目标 2）定义 TNK1 控制的信号级联。 STAT1 介导的丝氨酸磷酸化，以及（目标 3）确定 TNK1 在肝脏抗病毒先天免疫中的体内作用。研究将为病毒感染的前线防御提供新的见解，并有助于制定针对 HCV 感染和新出现的病毒性疾病的预防策略。