Receptor tyrosine kinase signaling and influenza viral RNA synthesis

受体酪氨酸激酶信号传导和流感病毒RNA合成

基本信息

批准号：
8241210
负责人：
YUYING LIANG
金额：
$ 19万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8241210
关键词：
Acute Affect Affinity Antiviral Agents Area Biological Assay Biology Cell Nucleus Complex DNA-Directed RNA Polymerase Data Development Drug resistance Epidemic Epithelial Cells Feedback Flu virus Frequencies Grant Human In Vitro Infectious Lung Disorder Influenza Influenza Therapeutic Integration Host Factors Intervention Lead Life Cycle Stages Lung Lung diseases Measures Mediating Morbidity - disease rate NGFR Protein Nerve Growth Factor Receptors Nerve Growth Factors Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Nuclear Nuclear Extract Nuclear Translocation Pharmaceutical Preparations Play Pneumonia Polymerase Protein Tyrosine Kinase Proteins Proteomics Public Health RNA chemical synthesis Receptor Protein-Tyrosine Kinases Research Resistance Role Signal Pathway Signal Transduction Specificity Staging Therapeutic Tissues Vaccines Variant Viral Virus Virus Diseases Virus Replication anti-influenza anti-influenza drug base combat drug resistant virus flu influenzavirus inhibitor/antagonist insight knock-down member mortality neurotrophic factor novel overexpression pandemic disease pathogen programs protein complex receptor reconstitution respiratory small hairpin RNA small molecule therapeutic target viral RNA

项目摘要

DESCRIPTION (provided by applicant): Influenza virus infection of the lungs causes a contagious acute respiratory disease that may result in severe complications such as pneumonia. Despite the active vaccine program, influenza virus remains a major global human pathogen causing annual epidemic and occasional pandemics with morbidity and mortality. Resistance to all available anti-flu drugs has been identified in influenza virus isolates, highlighting the need and urgency to develop novel anti-flu therapeutics. Host signaling pathways and host factors that are involved in the flu life cycle represent potential anti-viral targets, but the poor understanding of their functions and mechanisms in viral replication is a major barrier for the development of appropriate interventions. We have preliminary data to suggest that host nerve growth factor (NGF) receptor TrkA signaling plays important roles in the influenza viral replication at the step of viral RNA synthesis. TrkA is a member of neurotrophin receptor tyrosine kinases that also include TrkB and TrkC. It has been shown that neurotrophins and Trk receptors are expressed in many non-neuronal tissues including human lungs, but their pathophysiological roles in lungs remain largely unknown and their potential functions in the replication of respiratory viral pathogens have never been investigated. We hypothesize that host TrkA signaling is activated by influenza viral infection and, in a positive feedback loop, facilitates influenza viral replication by enhancing viral RNA synthesis. We propose to validate this novel hypothesis by determining the specific role of TrkA, B, and C in flu viral replication and RNA synthesis (Aim 1) and the mechanism of TrkA signaling involved in flu viral RNA synthesis (Aim 2). This exploratory study will evaluate a complete novel concept on the importance of host TrkA signaling in the influenza virus infection, provide the conceptual and factual basis for a subsequent full scale research effort on the mechanistic characterization of host signaling in the flu viral RNA synthesis, and potentially lead to the development of novel anti-viral therapeutics to treat this infectious lung disease. In a broader sense, it will shed important insights into an unknown area of how the Trk signaling in the lungs affect the replication of respiratory pathogens that may lead to novel broad-spectrum therapeutic measures against a class of infectious respiratory diseases. PUBLIC HEALTH RELEVANCE: Influenza is a contagious acute respiratory disease caused by influenza virus infection of the lungs, which may lead to severe complications such as pneumonia. Novel anti-flu drugs are urgently required as the current ones are quickly becoming out-of-date due to emergence of drug-resistant viral variants. We have preliminary data to suggest a novel functional role of host TrkA signaling in the influenza viral replication and viral RNA synthesis. We propose to evaluate and mechanistically characterize the role of host TrkA signaling pathways in the influenza viral RNA synthesis. These studies may lead to the identification of novel drugs against a class of infectious respiratory diseases.

描述（由申请人提供）：肺部流感病毒感染会引起传染性急性呼吸道疾病，可能导致肺炎等严重并发症。尽管有积极的疫苗计划，流感病毒仍然是全球主要的人类病原体，导致每年流行和偶尔发生大流行，并导致发病率和死亡率。已在流感病毒分离株中发现了对所有可用抗流感药物的耐药性，这凸显了开发新型抗流感疗法的必要性和紧迫性。流感生命周期中涉及的宿主信号通路和宿主因子代表了潜在的抗病毒靶点，但对其在病毒复制中的功能和机制了解甚少，这是制定适当干预措施的主要障碍。我们的初步数据表明，宿主神经生长因子 (NGF) 受体 TrkA 信号在流感病毒复制的病毒 RNA 合成步骤中发挥重要作用。 TrkA 是神经营养蛋白受体酪氨酸激酶的成员，还包括 TrkB 和 TrkC。研究表明，神经营养蛋白和 Trk 受体在包括人肺在内的许多非神经元组织中表达，但它们在肺中的病理生理学作用仍然很大程度上未知，并且它们在呼吸道病毒病原体复制中的潜在功能从未被研究过。我们假设宿主 TrkA 信号传导被流感病毒感染激活，并在正反馈循环中通过增强病毒 RNA 合成来促进流感病毒复制。我们建议通过确定 TrkA、B 和 C 在流感病毒复制和 RNA 合成中的具体作用（目标 1）以及 TrkA 信号传导参与流感病毒 RNA 合成的机制（目标 2）来验证这一新假设。这项探索性研究将评估关于宿主 TrkA 信号传导在流感病毒感染中的重要性的全新概念，为后续关于流感病毒 RNA 合成中宿主信号传导机制表征的全面研究工作提供概念和事实基础，以及可能会导致开发新型抗病毒疗法来治疗这种传染性肺部疾病。从更广泛的意义上讲，它将为肺部 Trk 信号传导如何影响呼吸道病原体复制的未知领域提供重要见解，这可能会导致针对一类传染性呼吸道疾病的新型广谱治疗措施。公共卫生相关性：流感是一种由流感病毒感染肺部引起的传染性急性呼吸道疾病，可能导致肺炎等严重并发症。由于耐药病毒变种的出现，现有的抗流感药物很快就会过时，因此迫切需要新型抗流感药物。我们有初步数据表明宿主 TrkA 信号在流感病毒复制和病毒 RNA 合成中具有新的功能作用。我们建议评估并从机制上表征宿主 TrkA 信号通路在流感病毒 RNA 合成中的作用。这些研究可能会导致针对一类传染性呼吸道疾病的新药的鉴定。