COVID-19: Understanding The Role of Corona Virus InducedDisruption Of Alveolar Type 2 Cell Function And SurfactantHomeostasis In The Pathogenesis Of COVID-19 AcuteRespiratory Distress Syndrome

COVID-19:了解冠状病毒引起的肺泡 2 型细胞功能和表面活性剂稳态破坏在 COVID-19 急性呼吸窘迫综合征发病机制中的作用

基本信息

  • 批准号:
    10744174
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-01-01 至 2023-09-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT The Severe Acute Respiratory Syndrome (SARS)-associated coronavirus 2 (SCoV2) is the cause of COVID-19 syndrome which is marked by a refractory acute lung injury that results in dramatic hypoxic respiratory failure and high mortality. Despite the recurrent health and economic devastation produced by novel coronaviruses (nCoV) over the past 20 years including SCoV2 as well as its predecessors SCoV1, and MERS-CoV, there remains a significant unmet need both for a clearer understanding of virus-host cell interactions as well as identification of new therapeutic targets. To address these issues with the ultimate goal of improving the health and outcomes of veterans with COVID-19, we have assembled a team of internationally recognized scientists with expertise in coronavirus virology and in lung biology coupled with a strong foundation of our own prior work on surfactant biology, lung injury, and fibrotic repair funded, in part, by the VA Merit Review program. Utilizing this expertise, this proposal is directed at filling in large knowledge gaps that exist in the pathogenesis of nCoV induced respiratory failure. The motivation for this investigation has been fueled by the recent recognition that the alveolar type 2 (AT2) epithelial cell of the distal lung has emerged as an important portal of entry for SCoV- 2. The central hypothesis of this application is that AT2 cells infected with nCoV acquire defects in surfactant biosynthesis/metabolism, activate cellular stress pathways, and develop alterations in progenitor cell function all of which promote hypoxic respiratory failure, persistent lung inflammation and injury, and impact recovery through effects on epithelial repair capacity. To test this, we will leverage an established murine model of CoV infection (MHV-1) with a pulmonary phenotype combined with reductionist studies supported by ex vivo infection of primary human AT2 cells obtained from a robust human lung pipeline with an already in hand SARS-CoV-2 isolate. Our experimental approach will interrogate these preclinical models using tools and reagents available in our program, to map the effect of CoV infection on distal lung cell populations with a focus on identifying and translating molecular mechanisms linking the disrupted AT2 function with altered surfactant biology and proinflammatory/profibrotic cell cross talk in the alveoilar niche. In Specific Aim 1, we will first define temporal changes in distal lung epithelial endophenotypes focusing on the ontogeny of the disruption of AT2 homeostasis by viral infection using a well characterized mouse model of MHV-1 lung infection. Using both unbiased approaches such as transcriptomic profiling as well as classical cell biology and biochemistry this aim will investigate CoV induced changes in surfactant metabolism/biophysical activity, AT2 cell stress (i.e. ER stress, proteasome dysfunction, autophagy malfunction, changes in mitochondrial dynamics/ / bioenergetics) and AT2 progenitor cell function. In Specific Aim 2, armed with this “functional map” of the mouse CoV-lung and aberrant AT2 behaviors, we will translate the identified lead targets and mechanisms to human AT2 cells utilizing both primary AT2 cultures as well as precision cut lung slices (PCLS) infected with SARS-CoV-2. The research design involves the analysis of virus-dependent AT2 surfactant protein and lipid metabolism, interrogation of AT2 cell quality control pathways, and functional evaluation of AT2 progenitor function phenotypes in the SCoV-2 infected human epithelial cells. By understanding the path to epithelial injury / dysfunction from nCoV, the mechanisms and affected lung cell populations identified using these models will improve the understanding of sCOV2/COVID- 19 syndrome, promote identification of new target pathways, and can be cross-purposed to test emerging therapies for both the current and future nCoV pandemics.
摘要

项目成果

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MICHAEL FRANCIS BEERS其他文献

MICHAEL FRANCIS BEERS的其他文献

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{{ truncateString('MICHAEL FRANCIS BEERS', 18)}}的其他基金

Surfactant Protein C Mouse Models: A Fit For Purpose Preclinical Platform For Advancing Discovery In And Treatment Of Idiopathic Pulmonary Fibrosis
表面活性剂蛋白 C 小鼠模型:一个适合目的的临床前平台,可促进特发性肺纤维化的发现和治疗
  • 批准号:
    10321882
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Surfactant Protein C Mouse Models: A Fit For Purpose Preclinical Platform For Advancing Discovery In And Treatment Of Idiopathic Pulmonary Fibrosis
表面活性剂蛋白 C 小鼠模型:一个适合目的的临床前平台,可促进特发性肺纤维化的发现和治疗
  • 批准号:
    10542732
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
COVID-19: Understanding The Role of Corona Virus InducedDisruption Of Alveolar Type 2 Cell Function And SurfactantHomeostasis In The Pathogenesis Of COVID-19 AcuteRespiratory Distress Syndrome
COVID-19:了解冠状病毒引起的肺泡 2 型细胞功能和表面活性剂稳态破坏在 COVID-19 急性呼吸窘迫综合征发病机制中的作用
  • 批准号:
    10152248
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Surfactant Protein C Mouse Models: A Fit For Purpose Preclinical Platform For Advancing Discovery In And Treatment Of Idiopathic Pulmonary Fibrosis
表面活性剂蛋白 C 小鼠模型:一个适合目的的临床前平台,可促进特发性肺纤维化的发现和治疗
  • 批准号:
    10025851
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
COVID-19: Understanding The Role of Corona Virus InducedDisruption Of Alveolar Type 2 Cell Function And SurfactantHomeostasis In The Pathogenesis Of COVID-19 AcuteRespiratory Distress Syndrome
COVID-19:了解冠状病毒引起的肺泡 2 型细胞功能和表面活性剂稳态破坏在 COVID-19 急性呼吸窘迫综合征发病机制中的作用
  • 批准号:
    10367948
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Alveolar Epithelial Cell Dysfunction in Pulmonary Fibrosis: Leveraging SFTPC Mutations for Discovery of Molecular and Cellular Targets
肺纤维化中的肺泡上皮细胞功能障碍:利用 SFTPC 突变发现分子和细胞靶点
  • 批准号:
    10165806
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Alveolar Epithelial Cell Dysfunction in Pulmonary Fibrosis: Leveraging SFTPC Mutations for Discovery of Molecular and Cellular Targets
肺纤维化中的肺泡上皮细胞功能障碍:利用 SFTPC 突变发现分子和细胞靶点
  • 批准号:
    10407546
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Biosynthesis and Trafficking of Surfactant Protein C In Health and Disease
表面活性剂蛋白 C 在健康和疾病中的生物合成和运输
  • 批准号:
    8559147
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Biosynthesis and Trafficking of Surfactant Protein C In Health and Disease
表面活性剂蛋白 C 在健康和疾病中的生物合成和运输
  • 批准号:
    8731968
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Biosynthesis and Trafficking of Surfactant Protein C In Health and Disease
表面活性剂蛋白 C 在健康和疾病中的生物合成和运输
  • 批准号:
    9281865
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:

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