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: 10744174
• 负责人: MICHAEL FRANCIS BEERS
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10744174
• 关键词: 2019-nCoV; ACE2; Acceleration; Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Affect; Alveolar; Anabolism; Apoptosis; Autophagocytosis; Behavior; Berlin; Big Data; Biochemistry; Bioenergetics; Biology; Biophysics; COVID-19; COVID-19 pandemic; COVID-19 pathogenesis; Caring; Catalogs; Cell Communication; Cell Ontogeny; Cell model; Cell physiology; Cells; Cellular Stress; Cellular biology; Characteristics; Cicatrix; Clinical; Coronavirus; Coronavirus Infections; Coupled; Data; Defect; Development; Disease; Dissociation; Distal; Distress; Economics; Epidemic; Epithelial Cells; Epithelium; Evaluation; Foundations; Functional disorder; Funding; Future; Genetic; Goals; Growth; Hand; Health; Homeostasis; Human; Hypoxemia; Hypoxemic Respiratory Failure; Impairment; In Vitro; Infection; Inflammatory; Innate Immune Response; International; Investigation; Knowledge; Lead; Link; Lung; Lung Capacity; Lung infections; Maintenance; Maps; Mediating; Metabolism; Middle East Respiratory Syndrome Coronavirus; Mitochondria; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Motivation; Mus; Natural Immunity; Organ; Organoids; Outcome; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Physiological; Population; Positioning Attribute; Pre-Clinical Model; Program Reviews; Proteins; Pulmonary Inflammation; Pulmonary Surfactants; Quality Control; Radiology Specialty; Reagent; Recovery; Recurrence; Refractory; Reporting; Research Design; Residual state; Respiratory Disease; Respiratory Failure; Respiratory Mechanics; Role; SARS coronavirus; SARS-CoV-2 infection; Scientist; Severities; Signal Pathway; Slice; Survivors; Syndrome; System; Techniques; Technology; Testing; Therapeutic; Translating; Ubiquitin; Veterans; Viral; Virus; Virus Diseases; Work; alveolar epithelium; arm; biological adaptation to stress; coronavirus pandemic; cytokine; effective therapy; endophenotype; endoplasmic reticulum stress; epithelial injury; epithelial repair; experience; fibrotic lung; immunopathology; improved; in vivo; induced pluripotent stem cell; lipid metabolism; lung injury; lung repair; mortality; mouse model; multicatalytic endopeptidase complex; new therapeutic target; novel; novel coronavirus; novel strategies; pandemic disease; pharmacologic; pre-clinical; progenitor; programs; protein kinase R; protein metabolism; receptor; repaired; respiratory; response; senescence; stem cell function; stem cells; surfactant; tool; transcriptomic profiling; transcriptomics; virology

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