R35HL160770

Mechanisms of Alveolar Homeostasis, Injury, Regeneration, and Fibrosis - 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 for these diseases are limited, primarily due to our incomplete understanding of disease pathogenesis. These diseases arise from injury to the alveolar epithelium with ineffective 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, as well as 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, along 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, and severe acute injury results in barrier permeability, leading to ARDS. Clinical recovery requires epithelial regeneration. In IPF, repetitive epithelial injury with impaired regeneration leads to 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 and then differentiate into AEC1s. Mechanisms of AEC2 proliferation have been identified by us and others. Additionally, 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 their persistence 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, as well as the mechanisms by which transitional cells persist and promote fibrosis in IPF, are unknown.

In this project, we will explore the mechanisms of alveolar cell-cell crosstalk that maintain homeostasis and promote physiologic regeneration, as well as 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 the mechanism. The proposed work aims to 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.

Regents Of The University Of Michigan

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Ann Arbor, Michigan 481091276 United States

Single Zip Code

NHLBI Emerging Investigator Award (EIA) (R35 Clinical Trial Optional) (RFA-HL-20-012)

Amendment Since initial award the total obligations have increased 281% from $911,296 to $3,471,063.