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Pulmonary pathophysiology sub-phenotypes of pneumonia

肺炎的肺部病理生理学亚表型

基本信息

批准号：
10559704
负责人：
JOSEPH P MIZGERD
金额：
$ 82.3万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
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/10559704
关键词：
2019-nCoV Address Alveolar Autopsy Biological Biological Process Biology Blood specimen Board Certification COVID-19 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 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 Streptococcus pneumoniae Structure of parenchyma of lung System Testing Tissue Sample Tissues Transcript United States National Institutes of Health adverse outcome cell type cohort disease phenotype empowerment feature selection high risk population improved in vivo innovation insight microbial mouse model precision medicine prevent response segregation single nucleus RNA-sequencing tool transcriptomics

项目摘要

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.

肺炎可导致包括住院、重症监护和死亡在内的不良后果。主机响应为