Molecular and Cellular Interactions Between Cigarette Smoke Exposure and RSV

香烟烟雾暴露与 RSV 之间的分子和细胞相互作用

基本信息

批准号：
8668779
负责人：
Charles S Dela Cruz
金额：
$ 13.39万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-05 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8668779
关键词：
Address Adult Advisory Committees Air Antiviral Agents Biological Models Bronchiolitis Calculi Cessation of life Child Chronic Chronic Obstructive Airway Disease Defect Disease Elderly Environment Exposure to Fibrosis Future Genetic Transcription Grant Hospitalization Human Immune Immunity Incidence Individual Infant Infection Inflammation Inflammatory Inflammatory Response Influenza Influenza A Virus, H1N1 Subtype Interferon Type I Interferon-alpha Interferon-beta Interferons Life Lung Lung Inflammation Mediating Mentors Mentorship Metabolic Clearance Rate Military Personnel Molecular Morbidity - disease rate Mus Natural Immunity Nucleic Acids Nucleoproteins Pathogenesis Pathology Pathway interactions Patients Pneumonia Production RNA Recruitment Activity Relative (related person)Research Respiratory Syncytial Virus Infections Respiratory Tract Infections Respiratory physiology Respiratory syncytial virus Risk Factors Role Rosa Severities Smoker Source TLR3 gene Translational Research Universities Viral Virus Virus Diseases Vocational Guidance Work alveolar destruction career cigarette smoke-induced cigarette smoking cytokine experience helicase influenza epidemic mortality mouse model novel novel therapeutic intervention pathogen professor programs receptor response

项目摘要

DESCRIPTION (provided by applicant): Cigarette smoke (CS) exposure is associated with increased incidence and severity of airway infections in both children and the elderly. Respiratory syncytial virus (RSV) causes severe bronchiolitis in infants and worsens disease course in chronic obstructive lung disease (COPD) exacerbation in adults. The molecular mechanisms of CS exposure on viral immunity and pathogenesis are not well studied. My studies show that CS exposure has an impressive ability to regulate the innate immunity in the lung after RSV infection. CS enhances the inflammation, alveolar destruction and airway fibrosis caused by RSV. These effects are mediated by type I interferon (IFN) and RIG-like helicase (RLH) antiviral innate immune pathways. CS exposure also results in the persistence of RSV nucleic acids, but not clearance of live virus, in the lung, which we hypothesize chronically activates the RLH innate immune pathways that leads to chronic inflammation. This novel mechanistic pathway may explain the heightened inflammatory response and worsening lung functions in COPD patients with multiple virally-induced exacerbations, and the chronic lung inflammation seen in stable COPD patients. Hypotheses - CS interacts in a synergistic manner with live or UV-inactivated RSV to increase inflammation and remodeling. These interactions are mediated by viral nucleic acid activation of the non-TLR, RIG-like helicase (RLH) innate immune pathway. CS exposure does not alter the clearance of live virus, but allows for the persistence of viral nucleic acids, which contribute to the chronic inflammation and remodeling responses in COPD via RLH pathway activation. Aim 1: Determine if the synergistic interaction between CS and RSV are mediated by RLH pathways. Aim 2: Define the role(s) of type I interferons (IFNa, IFNb) and the type 1 IFN pathway in the enhanced inflammatory and remodeling responses induced by CS and RSV. Aim 3: Define the type I interferon-independent mechanism(s) by which CS exposure enhances the inflammatory response to UV-inactivated RSV. Aim 4: Define the effects of CS exposure on the clearance of live virus and viral nucleic acids in CS- and room air (RA)-exposed lungs. This grant proposes a research mentorship program at Yale University under the primary sponsorship of Professor Jack Elias, a world leader in lung inflammation and fibrosis. Professor George Miller, a recognized leader in viral transcription and replication will serve as co-mentor. We have also enlisted the expertise of three RNA virologists, Drs. Peter Collins, Jeffrey Kahn, and Jack Rose. An advisory committee at Yale will provide scientific and career counseling. The proposed research program as outlined will provide an exciting scientific environment wherein Dr. Dela Cruz can launch his future independent academic career.

描述（由申请人提供）：烟烟（CS）暴露与儿童和老年人的气道感染的发病率和严重程度有关。呼吸道合胞病毒（RSV）导致婴儿严重的细支气管炎，并使成人慢性阻塞性肺病（COPD）恶化。 CS暴露于病毒免疫和发病机理上的分子机制尚未得到很好的研究。我的研究表明，CS暴露具有令人印象深刻的能力，可以调节RSV感染后肺部的先天免疫力。 CS增强了由RSV引起的炎症，肺泡破坏和气道纤维化。这些作用是由I型干扰素（IFN）和类似RIG样解旋酶（RLH）抗病毒先天免疫途径介导的。 CS暴露还导致肺中RSV核酸的持久性，但没有生存病毒的清除，我们假设这会长期激活RLH先天免疫途径，从而导致慢性炎症。这种新型的机械途径可能解释了多种病毒引起的病毒诱发的COPD患者的炎症反应增强和肺功能恶化，以及稳定的COPD患者中观察到的慢性肺部炎症。假设-CS与活或紫外线灭活的RSV以协同方式相互作用，以增加炎症和重塑。这些相互作用是由非TLR，rig样解旋酶（RLH）先天免疫途径的病毒核酸激活介导的。 CS暴露不会改变活病毒的清除率，而是允许病毒核酸的持久性，这会通过RLH途径激活通过RLH途径激活COPD中的慢性炎症和重塑反应。 AIM 1：确定CS和RSV之间的协同相互作用是否由RLH途径介导。 AIM 2：定义I型干扰素（IFNA，IFNB）的作用以及CS和RSV引起的增强炎症和重塑反应中的1型IFN途径。 AIM 3：定义I型干扰素无关的机制，通过该机制，CS暴露增强了对紫外线灭活RSV的炎症反应。 AIM 4：定义CS暴露对CS和房间暴露肺（RA）肺中活病毒和病毒核酸清除的影响。该赠款提出了耶鲁大学的研究指导计划，该计划是杰克·埃里亚斯（Jack Elias）教授的主要赞助，杰克·埃里亚斯（Jack Elias）是肺部炎症和纤维化的世界领导者。乔治·米勒（George Miller）教授是病毒转录和复制的公认领导者，将担任联合委员。我们还招募了三位RNA病毒学家Drs的专业知识。彼得·柯林斯，杰弗里·卡恩和杰克·罗斯。耶鲁大学的咨询委员会将提供科学和职业咨询。概述的拟议研究计划将提供一个令人兴奋的科学环境，其中德拉·克鲁兹（Dela Cruz）博士可以启动他未来的独立学术生涯。