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

• 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
• 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

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）：肺的流感病毒感染引起传染性的急性呼吸道疾病，可能导致严重的并发症，例如肺炎。尽管有活跃的疫苗计划，但流感病毒仍然是全球主要的人类病原体，导致每年流行病和偶尔出现发病率和死亡率。在流感病毒分离株中已经鉴定出对所有可用抗FLU药物的耐药性，强调了开发新型抗FLU疗法的需求和紧迫性。流感生命周期中涉及的宿主信号通路和宿主因素代表了潜在的抗病毒靶标，但是对病毒复制中其功能和机制的不良理解是发展适当干预措施的主要障碍。我们有初步数据，表明宿主神经生长因子（NGF）受体TRKA信号在病毒RNA合成阶段在流感病毒复制中起重要作用。 TRKA是神经营养蛋白受体酪氨酸激酶的成员，其中还包括TRKB和TRKC。已经表明，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作用在很大程度上尚不清楚，并且从未研究过它们在呼吸病毒病原体复制中的潜在功能。我们假设宿主TRKA信号传导被流感病毒感染激活，并且在正面反馈环中，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合成中的特定作用来验证这一新假设（AIM 1）以及参与流感病毒RNA合成的TRKA信号的机制（AIM 2）。这项探索性研究将评估一个完整的小说概念，内容涉及宿主TRKA信号在流感病毒感染中的重要性，为随后在流感病毒RNA合成中的机械表征的全面研究工作提供概念和事实基础，并有可能导致这种新型抗病毒治疗疗法的发展来治疗这种不受欢迎的疾病。从广义上讲，它将对未知领域进行重要见解，即肺中的TRK信号如何影响呼吸道病原体的复制，这可能导致针对一类传染性呼吸道疾病的新型广谱治疗方法。 公共卫生相关性：流感是由肺流感病毒感染引起的一种具有传染性的急性呼吸道疾病，这可能导致严重的并发症，例如肺炎。由于抗药性病毒变异的出现，当前的抗FLU药物是迫切需要的，因为目前的药物正迅速过时。我们拥有初步数据，以提出宿主TRKA信号在流感病毒复制和病毒RNA合成中的新功能作用。我们建议评估并机械地表征宿主TRKA信号通路在流感病毒RNA合成中的作用。这些研究可能导致针对一系列感染性呼吸系统疾病的新药物鉴定。