Elucidating How Tri-phosphatase DUSP11 Controls HCV Infection and Hepatocyte Inflammation

阐明三磷酸酶 DUSP11 如何控制 HCV 感染和肝细胞炎症

• 批准号: 9753109
• 负责人: Glenn C Randall
• 金额: $ 45.87万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753109
• 关键词: Address; Antiviral Agents; Autoimmune Diseases; Binding; Biochemical; Biology; Cells; Code; Communicable Diseases; Complex; Cultured Cells; Data; Disease; Disease Progression; Future; Goals; HCV Liver Disease; Health; Hepatic; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Immune; Immune System Diseases; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Knock-out; Knockout Mice; Knowledge; Liver; Liver diseases; Mediating; MicroRNAs; Mission; Molecular; National Institute of Allergy and Infectious Disease; National Institute of Diabetes and Digestive and Kidney Diseases; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Physiology; Primary carcinoma of the liver cells; Process; Proteins; Public Health; RNA; RNA triphosphatase; Research; Risk Factors; Technology; Testing; Therapeutic; Transcript; United States National Institutes of Health; Untranslated RNA; Vaccine Design; Viral; Viral Physiology; Virus; Virus Diseases; Virus Replication; Work; adaptive immune response; anti-hepatitis C; chronic infection; combat; design; experimental study; immunogenic; in vivo; innovation; liver inflammation; novel; nuclease; prevent; resistance mechanism; transcriptome sequencing; tripolyphosphate; viral RNA; viral resistance

PROJECT SUMMARY Both the clearance of hepatitis C virus (HCV) and its disease manifestations are associated with the inflammatory response. Yet, large gaps in knowledge exist about the factors that initiate inflammation and control HCV replication. There is an urgent need to fill these gaps because determining the mechanisms that control HCV infection and associated inflammation is imperative for understanding HCV-associated disease. The long-term goal of this collaborative team is to understand the mechanisms of HCV innate control and pathogenesis. Consistent with this goal, the overall objective in this proposal is to determine how the RNA triphosphatase DUSP11 is associated with control of both HCV infection and pro-inflammatory RNA transcripts. The central hypothesis is that DUSP11 promotes turnover of pro-inflammatory host and viral triphosphorylated transcripts, thereby reducing HCV replication and RNA-associated inflammation. The rationale for this proposed research is that, once it is known how DUSP11 functions in control of virus replication and host pro-inflammatory transcripts, this will advance understanding of the innate defenses against HCV, imperative for guiding future rational vaccine designs and for developing therapeutic strategies to address HCV-induced liver pathogenesis. Testing the central hypothesis and completing the objectives outlined in this proposal will be accomplished via the following two specific aims: 1) Determine the anti-HCV mechanism of DUSP11 in liver cells, and 2) Determine the function of DUSP11 in controlling inflammation associated with pro-inflammatory viral and host RNAs. Under the first aim, knockout approaches combined with cell, molecular and biochemical experiments will reveal how DUSP11 and its partners inhibit HCV virus infection and how the virus counters this restriction by binding the cellular microRNA, miR-122. Under the second aim, specialized high-throughput tri-phosphate-specific RNA sequencing technology combined with knockout mice will determine how DUSP11 controls inflammation associated with viral and host pro- inflammatory RNAs in cultured cells and in vivo. The contribution here is expected to be a detailed understanding of the mechanisms of how DUSP11 restricts HCV replication and modulates pro-inflammatory activities of viral and host RNAs during infection. These contributions will be significant because they are expected to have broad translational importance for understanding the activity and possible viral resistance mechanisms of current phase II anti-miR-122 HCV drugs as well as informing the interface of innate and adaptive immune response – key for rational vaccine design. The research proposed in this application is innovative because it represents a new and substantive departure from the status quo by focusing on DUSP11, a single protein that promotes both restriction of HCV and control of inflammation triggered by host and viral RNAs. The results from this proposed work will have a positive impact because they will expand understanding of HCV disease and likely guide the design of preventative and therapeutic strategies.

项目概要 丙型肝炎病毒（HCV）的清除及其疾病表现均与 然而，对于引发炎症和炎症反应的因素存在巨大的认识差距。 迫切需要填补这些空白，因为确定控制 HCV 复制的机制。 控制 HCV 感染和相关炎症对于了解 HCV 相关疾病至关重要。 该合作团队的长期目标是了解丙型肝炎病毒先天控制和控制的机制。 与这一目标一致，本提案的总体目标是确定 RNA 如何发生。 三磷酸酶 DUSP11 与 HCV 感染和促炎性 RNA 的控制相关 核心假设是 DUSP11 促进促炎宿主和病毒的更新。 三磷酸化转录本，从而减少 HCV 复制和 RNA 相关炎症。 这项拟议研究的基本原理是，一旦了解 DUSP11 如何在控制病毒方面发挥作用， 复制和宿主促炎症转录本，这将促进对先天防御的理解 对抗 HCV，指导未来合理的疫苗设计和制定治疗策略至关重要 解决 HCV 诱导的肝脏发病机制。测试中心假设并完成目标。 本提案中概述的目标将通过以下两个具体目标来实现： 1) 确定抗 HCV DUSP11在肝细胞中的作用机制，以及2)确定DUSP11控制炎症的功能 与促炎病毒和宿主 RNA 相关 在第一个目标下，结合了敲除方法。 通过细胞、分子和生化实验将揭示DUSP11及其伙伴如何抑制HCV病毒 感染以及病毒如何通过结合细胞 microRNA miR-122 来对抗这种限制。 第二个目标，专门的高通量三磷酸特异性RNA测序技术结合 敲除小鼠将确定 DUSP11 如何控制与病毒和宿主亲相关的炎症 培养细胞和体内的炎症 RNA 预计将是详细的。 了解 DUSP11 如何限制 HCV 复制和调节促炎症的机制 病毒和宿主 RNA 在感染过程中的活性将非常重要，因为它们是 预计对于理解活性和可能的​​病毒耐药性具有广泛的转化重要性 当前 II 期抗 miR-122 HCV 药物的机制以及告知先天和 适应性免疫反应——合理疫苗设计的关键 本申请提出的研究是。 创新，因为它代表着对现状的新的实质性偏离 DUSP11，一种单一蛋白质，可促进限制 HCV 并控制宿主引发的炎症 这项拟议工作的结果将产生积极影响，因为它们会扩大。 了解 HCV 疾病并可能指导预防和治疗策略的设计。