Pulmonary pathophysiology sub-phenotypes of pneumonia

肺炎的肺部病理生理学亚表型

• 批准号: 10446020
• 负责人: JOSEPH P MIZGERD
• 金额: $ 85.63万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446020
• 关键词: 2019-nCoV; Address; Alveolar; Autopsy; Biological; Biological Process; Biology; Blood specimen; COVID-19 pneumonia; Cell Nucleus; Cells; Cessation of life; Characteristics; Communities; Data Set; Development; Disease; Elderly; Elements; Etiology; Experimental Models; Floods; Functional disorder; Future; Gene Expression; Goals; Growth; Heterogeneity; Histopathology; Hospitalization; Human; Immune; Immune response; Immunity; Immunohistochemistry; Immunologics; Infection; Inflammation; Influenza; Injury; Intensive Care; Knowledge; Lead; Lung; Lung infections; Measures; Microscopic; Microscopy; Modeling; Molecular; Pathologist; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Pneumonia; Prospective cohort; Proteins; Pulmonary Pathology; Research Priority; Resolution; Sampling; Site; Slide; Small Nuclear RNA; Streptococcus pneumoniae; Structure of parenchyma of lung; System; Testing; Tissue Sample; Tissues; Transcript; United States National Institutes of Health; adverse outcome; base; cell type; cohort; disease phenotype; empowered; exhaustion; high risk population; improved; in vivo; innovation; insight; microbial; mouse model; precision medicine; prevent; response; tool; transcriptome sequencing; transcriptomics

Pneumonia causes adverse outcomes including hospitalization, intensive care, and death. Host response is pivotal, with immune activities and cell dysfunctions responsible for pathophysiologies including but not limited to excessive microbial growth, alveolar flooding, and septal destruction. Many diverse biological pathways can lead to adverse outcomes within the infected lungs. A better understanding of the immunological and cellular activities occurring inside severely infected lungs is needed, to distinguish sub-phenotypes of disease and improve the development and application of host-directed therapies. In the proposed studies, we will leverage large sets of post-mortem human pneumonic lung samples collected via rapid autopsy for defining pneumonia sub-phenotypes based on their pulmonary pathobiology. We will integrate semi-quantitative histopathology (scored by board-certified pathologists), quantitative multiplex fluorescent immunohistochemistry (mfIHC; to enumerate and localize immune cells within these lungs), and single nuclei RNA sequencing (snRNA-seq; to broaden and deepen cell and molecular resolution of these lungs) in order to differentiate distinct lung pathobiologies during pneumonia. In addition, we will examine multiple current and emergent experimental models of severe pneumonia to determine which if any recapitulate elements of these pulmonary pathobiologies. We propose to test the central hypothesis that severe pneumonias cluster into distinct lung pathobiology sub-phenotypes, by pursuing the following specific aims: Aim 1) To test whether humans dying with pneumonia segregate into lung pathology sub-phenotypes, using rapid autopsy samples analyzed via histopathologic scoring and quantitative mfIHC. Aim 2) To validate and elucidate pneumonia sub- phenotypes using an independent cohort with microscopy matched to snRNA-seq for defining cell-types and cell-specific gene expression in infected human lungs. Aim 3) To test whether established and emerging experimental models of severe pneumonia recapitulate some and which elements of human pulmonary pathobiology. The proposed studies will be significant for generating discoveries from lung and blood samples of pneumonia cases in elderly subjects, an especially high risk group for pneumonia. Proposed studies will increase resolution into the heterogeneity of pneumonia, a currently pressing research priority. Results will reveal whether sub-phenotypes or select features measured within the pneumonic lungs differ between pneumonias caused by pneumococcus, influenza, and SARS-CoV-2. Defining sub-types of pneumonia with distinct molecular and cellular changes in the lungs will improve the development and use of host-directed approaches for treating or preventing pneumonia.

肺炎会导致不良后果，包括住院、重症监护和死亡。主机响应是 关键，免疫活性和细胞功能障碍导致病理生理学，包括但不限于 过度的微生物生长肺泡灌洗和隔膜破坏。许多不同的生物途径可以 导致肺部感染的不良后果。更好地了解免疫和细胞 需要在严重感染的肺内发生的活动，以区分疾病的亚表型， 促进宿主导向疗法的开发和应用。在拟议的研究中，我们将利用 通过快速尸检收集的大量尸检人肺炎肺样本用于确定肺炎 基于其肺部病理学的亚表型。我们将结合半定量组织病理学 （由委员会认证的病理学家评分），定量多重荧光免疫组织化学（mfIHC; 计数和定位这些肺内的免疫细胞），以及单核RNA测序（snRNA-seq; 扩大和加深这些肺的细胞和分子分辨率）以区分不同的肺 肺炎期间的病理学此外，我们还将研究多个当前和紧急的实验 严重肺炎的模型，以确定哪些，如果有的话，概括这些肺的元素 病理生物学我们建议测试中心假设，即严重肺炎集群成不同的 肺病理生物学亚表型，通过追求以下具体目标：目的1）测试人类是否 使用快速尸检样本分析， 通过组织病理学评分和定量mfIHC。目的2）验证和阐明肺炎亚组- 使用与snRNA-seq匹配的显微镜检查的独立队列来确定细胞类型， 细胞特异性基因在受感染的人肺中的表达。目标3）测试是否已建立和正在形成 重症肺炎的实验模型概括了人类肺的一些元素， 病理生物学拟议中的研究将对从肺部和血液样本中产生发现具有重要意义 老年受试者中的肺炎病例，这是肺炎的特别高风险群体。拟议的研究将 提高对肺炎异质性的分辨率，这是目前迫切的研究重点。结果将 揭示在肺炎肺内测量的亚表型或选择特征是否在 肺炎球菌、流感和SARS-CoV-2引起的肺炎。定义肺炎的亚型 肺中不同的分子和细胞变化将改善宿主定向的 治疗或预防肺炎的方法。