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

基本信息

批准号：
10199990
负责人：
Glenn C Randall
金额：
$ 44.95万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199990
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 design experimental study immunogenic in vivo innovation liver inflammation novel nuclease prevent resistance mechanism transcriptome sequencing tripolyphosphate viral RNA viral resistance

项目摘要

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.

项目摘要丙型肝炎病毒（HCV）的清除及其疾病表现都与炎症反应。然而，知识中存在很大的差距，涉及启动注射和控制HCV复制。迫切需要填补这些空白，因为确定的机制控制HCV感染和相关感染对于理解与HCV相关疾病至关重要。这个合作团队的长期目标是了解HCV先天控制和发病。与这个目标一致，该提案的总体目标是确定RNA如何三磷酸酶DUSP11与HCV感染和促炎RNA的控制有关成绩单。中心假设是DUSP11促进促炎宿主和病毒的营业额三磷酸化的转录本，从而减少了HCV复制和与RNA相关的注射。这这项拟议的研究的理由是，一旦知道了DUSP11如何控制病毒复制和主机亲炎笔录，这将提高对先天防御的理解反对HCV，必须指导未来的理性疫苗设计和制定治疗策略解决HCV诱导的肝发病机理。测试中心假设并完成目标该提案中概述的将通过以下两个具体目的完成：1）确定抗HCV DUSP11在肝细胞中的机制，2）确定DUSP11控制炎症的功能与促炎病毒和宿主RNA有关。在第一个目标下，淘汰赛方法结合在一起使用细胞，分子和生化实验将揭示DUSP11及其伴侣如何抑制HCV病毒感染以及病毒如何通过结合细胞microRNA来抵消这种限制，miR-122。在第二个目的，专门的高通量三磷酸特异性RNA测序技术与敲除小鼠将确定DUSP11如何控制与病毒和宿主促进相关的感染培养细胞和体内的炎症性RNA。预计这里的贡献将是详细的了解dusp11如何限制HCV复制并调节促炎的机制感染期间病毒和宿主RNA的活动。这些贡献将是重要的，因为它们是预计将对理解活动和可能的病毒抗性具有广泛的翻译重要性当前II期抗MIR-122 HCV药物的机制，并告知先天和自适应免疫反应 - 理性疫苗设计的关键。该应用程序提出的研究是创新性是因为它通过关注而代表了与现状的新事物相去甚远 DUSP11，一种促进HCV限制和对宿主触发的注射的控制的单一蛋白质和病毒RNA。这项拟议工作的结果将产生积极的影响，因为它们将扩大了解HCV疾病，并可能指导预防和治疗策略的设计。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

DUSP11 and triphosphate RNA balance during virus infection.

DOI：
10.1371/journal.ppat.1009145
发表时间：
2021-01
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Choi JH;Sullivan CS
通讯作者：
Sullivan CS

DUSP11-mediated control of 5'-triphosphate RNA regulates RIG-I sensitivity.

DOI：
10.1101/gad.340604.120
发表时间：
2020-12-01
期刊：
Genes & development
影响因子：
10.5
作者：
Choi JH;Burke JM;Szymanik KH;Nepal U;Battenhouse A;Lau JT;Stark A;Lam V;Sullivan CS
通讯作者：
Sullivan CS