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:
    8470223
  • 负责人:
  • 金额:
    $ 13.39万
  • 依托单位:
  • 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

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):香烟烟雾(CS)暴露与儿童和老年人气道感染的发生率和严重程度增加相关。呼吸道合胞病毒(RSV)可引起婴儿严重的细支气管炎,并可导致成人慢性阻塞性肺疾病(COPD)加重。CS暴露对病毒免疫和发病机制的分子机制还没有很好的研究。我的研究表明,CS暴露具有令人印象深刻的调节RSV感染后肺部先天免疫的能力。CS增强RSV引起的炎症、肺泡破坏和气道纤维化。这些作用由I型干扰素(IFN)和RIG样解旋酶(RLH)抗病毒先天免疫途径介导。CS暴露还导致RSV核酸在肺中的持续存在,但不清除活病毒,我们假设其慢性激活RLH先天免疫途径,导致慢性炎症。这种新的机制途径可以解释COPD患者多次病毒诱导的急性加重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以协同方式与活的或UV灭活的RSV相互作用,以增加炎症和重塑。这些相互作用由病毒核酸激活非TLR、RIG样解旋酶(RLH)先天免疫途径介导。CS暴露不会改变活病毒的清除,但允许病毒核酸的持续存在,这有助于通过RLH途径激活COPD中的慢性炎症和重塑反应。目的1:确定CS和RSV之间的协同相互作用是否由RLH途径介导。目标二:定义I型干扰素(IFNa、IFNb)和I型IFN途径在CS和RSV诱导的炎症和重塑反应增强中的作用。目的3:确定CS暴露增强对UV灭活RSV的炎症反应的I型干扰素非依赖性机制。目的4:确定CS暴露对CS和室内空气(RA)暴露肺中活病毒和病毒核酸清除的影响。这项资助计划在耶鲁大学进行一项研究导师计划,主要由肺部炎症和纤维化领域的世界领导者Jack Elias教授赞助。教授乔治米勒,在病毒转录和复制公认的领导者将担任共同导师。我们还邀请了三位RNA病毒学家,彼得·柯林斯博士、杰弗里·卡恩博士和杰克·罗斯博士。耶鲁大学的一个咨询委员会将提供科学和职业咨询。拟议的研究计划概述将提供一个令人兴奋的科学环境,德拉克鲁兹博士可以启动他未来的独立学术生涯。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Charles S Dela Cruz其他文献

Charles S Dela Cruz的其他文献

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{{ truncateString('Charles S Dela Cruz', 18)}}的其他基金

Reciprocal brain-lung responses in post-stroke pneumonia
中风后肺炎的脑肺交互反应
  • 批准号:
    10754060
  • 财政年份:
    2023
  • 资助金额:
    $ 13.39万
  • 项目类别:
Viral and immune-mediated CNS pathology during SARS-CoV-2 infection
SARS-CoV-2 感染期间病毒和免疫介导的中枢神经系统病理学
  • 批准号:
    10554829
  • 财政年份:
    2020
  • 资助金额:
    $ 13.39万
  • 项目类别:
MAVS-Mediated Pulmonary Inflammation and Injury Response During Cigarette Smoke Exposure and Influenza Viral Infection and in COPD
香烟烟雾暴露和流感病毒感染以及 COPD 期间 MAVS 介导的肺部炎症和损伤反应
  • 批准号:
    9780742
  • 财政年份:
    2019
  • 资助金额:
    $ 13.39万
  • 项目类别:
MAVS-Mediated Pulmonary Inflammation and Injury Response During Cigarette Smoke Exposure and Influenza Viral Infection and in COPD
香烟烟雾暴露和流感病毒感染以及 COPD 期间 MAVS 介导的肺部炎症和损伤反应
  • 批准号:
    10292925
  • 财政年份:
    2019
  • 资助金额:
    $ 13.39万
  • 项目类别:
MAVS-Mediated Pulmonary Inflammation and Injury Response During Cigarette Smoke Exposure and Influenza Viral Infection and in COPD
香烟烟雾暴露和流感病毒感染以及 COPD 期间 MAVS 介导的肺部炎症和损伤反应
  • 批准号:
    10045508
  • 财政年份:
    2019
  • 资助金额:
    $ 13.39万
  • 项目类别:
MAVS-Mediated Pulmonary Inflammation and Injury Response During Cigarette Smoke Exposure and Influenza Viral Infection and in COPD
香烟烟雾暴露和流感病毒感染以及 COPD 期间 MAVS 介导的肺部炎症和损伤反应
  • 批准号:
    10515290
  • 财政年份:
    2019
  • 资助金额:
    $ 13.39万
  • 项目类别:
Host-Pneumococcal Interaction in the Lung
肺部宿主与肺炎球菌的相互作用
  • 批准号:
    8966696
  • 财政年份:
    2014
  • 资助金额:
    $ 13.39万
  • 项目类别:
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
  • 批准号:
    7953132
  • 财政年份:
    2010
  • 资助金额:
    $ 13.39万
  • 项目类别:
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
  • 批准号:
    8668779
  • 财政年份:
    2010
  • 资助金额:
    $ 13.39万
  • 项目类别:
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
  • 批准号:
    8277248
  • 财政年份:
    2010
  • 资助金额:
    $ 13.39万
  • 项目类别:

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