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Mechanisms of Alveolar Homeostasis, Injury, Regeneration, and Fibrosis

肺泡稳态、损伤、再生和纤维化的机制

基本信息

批准号：
10571931
负责人：
Rachel Lynne Zemans
金额：
$ 89.84万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2022-03-01 至 2029-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10571931
关键词：
Acute Acute Respiratory Distress Syndrome Alveolar Alveolar Cell Alveolar Macrophages Alveolus Automobile Driving Cells Chronic Chronic lung disease Clinical Collaborations Dedications Defect Development Disease Epithelial Cell Proliferation Epithelial Cells Fibroblasts Fibrosis Funding Health Homeostasis Human Impairment Injury Investigation Knowledge Lung diseases Mentorship Mission Molecular Morbidity - disease rate Mus Natural regeneration Nature Organism Pathogenesis Pathologic Permeability Physiological Process Pulmonary Fibrosis Recovery Services Time Transitional Cell United States National Institutes of Health Work alveolar epithelium alveolar homeostasis effective therapy epithelial injury epithelium regeneration idiopathic pulmonary fibrosis knockout gene lung injury mortality mouse model novel novel therapeutics progenitor regenerative

项目摘要

PROJECT SUMMARY Acute and chronic parenchymal lung diseases, such as the acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF), are associated with significant morbidity and mortality. Therapies are limited, largely due to our incomplete understanding of disease pathogenesis. These diseases arise from injury to the alveolar epithelium with ineffectual regeneration. In accordance with the NIH mission to “seek fundamental knowledge about the nature…of living systems and apply that knowledge to enhance health”, we aim to identify mechanisms by which alveolar homeostasis is maintained, disrupted during injury, and restored during physiologic regeneration and how these processes go awry in the pathogenesis of ARDS and IPF. The normal alveolus consists of alveolar type 2 epithelial cells (AEC2s) and AEC1s, which form a tight barrier, with quiescent fibroblasts and alveolar macrophages. The molecular mechanisms of cell-cell crosstalk that maintain alveolar quiescence during homeostasis are poorly understood. During lung injury, AECs die. Severe acute injury results in barrier permeability, leading to ARDS; clinical recovery requires epithelial regeneration. In IPF, repetitive epithelial injury with impaired regeneration begets fibrosis. However, the mechanisms underlying physiologic regeneration and how it is impaired in the pathogenesis of IPF are incompletely understood. AEC2s are the primary progenitor responsible for physiologic alveolar regeneration. AEC2s proliferate, then differentiate into AEC1s. We and others have identified mechanisms of AEC2 proliferation. Moreover, we were the first to identify a novel transitional cell state transiently assumed by regenerating AEC2s before differentiating into AEC1s. We also found that transitional cells persist in pulmonary fibrosis, suggesting that persistence of transitional cells may be the critical regenerative defect driving fibrosis. However, the mechanisms that induce AEC2s to assume the transitional state and transitional cells to differentiate into AEC1s during physiologic regeneration and by which transitional cells persist and promote fibrosis in IPF are unknown. Here, we will explore the mechanisms of alveolar cell-cell crosstalk that maintain homeostasis and promote physiologic regeneration and how these mechanisms go awry in ARDS and fibrosis. We will use lineage tracing combined with AEC2-specific inducible gene knockout in mouse models of homeostasis, injury, physiologic regeneration, and fibrosis. Cultured human and murine AECs will be used to dissect mechanism. The proposed work will fill fundamental gaps in our understanding of alveolar homeostasis and physiologic and pathologic regeneration and overcome critical barriers to the development of novel therapies for ARDS and IPF. The funding will also support the pursuit of new lines of investigation and the dedication of appropriate time and energy into collaborations, professional service, and mentorship.

项目总结