Delineating the role of let-7 microRNA on lung AT2 cell homeostasis, alveolar regeneration, and interstitial lung disease

项目总结

Project Summary Interstitial lung diseases (ILDs) including Idiopathic Pulmonary Fibrosis (IPF) are associated with significant morbidity and mortality. Treatment options for patients with ILD are limited by a lack of understanding of the pathophysiologic mechanisms. Alveolar type 2 (AT2) cells, the main epithelial progenitor stem cell population in the lung, are critically important in ILD pathophysiology as they regulate surfactant production and operate as stem cell progenitors for repair of alveoli after injury via generation of alveolar type 1 (AT1) cells. Disruptions to the DNA, protein, organellar quality control, and cell metabolism have all been hypothesized to underlie AT2-cell driven ILD. Recent insights on the AT2 cell states and differentiation trajectories led to the discovery of primed and cycling AT2 (pAT2 and cAT2) cell subpopulation(s) and alveolar differentiation intermediate (ADI) cells, which convert into AT1 cells during lung injury. However, the global regulatory mechanisms that contribute to dysregulated AT2 cell homeostasis and the relationship to impaired AT2 progenitor stem cell renewal are not well understood. In preliminary work, we found that conditional inactivation of let-7 microRNA clusters specifically in alveolar AT2 cells in mice promotes spontaneous age-dependent parenchymal remodeling with features of ILD including pronounced septal alveolar thickening, fibroblastic foci with collagen deposition and pronounced alveolitis. We also found that let-7 promotes hyperplasia of AT2 cells and the appearance of ADI transitional cells with a cellular senescence profile. Based on transcriptomic data hypothesize that the let-7 family of microRNAs serves as an essential coordinator of AT2 cell autophagy & lipid homeostasis, progenitor stem cell renewal, and AT1 differentiation. In this proposal, we will extend these exciting findings to (1) determine how the let-7 pathway regulates AT2 progenitor stem cell trajectories and cell differentiation dynamics during ILD; (2) determine how let-7 pathway impairs AT2 cell surfactant homeostasis and contributes to alterations in autophagy and lipid metabolism during ILD remodeling; and (3) identify mechanism(s) through which let-7 controls AT2 cell renewal in mice and humans. The project will elucidate a fundamental repair and regeneration process in the lung and pave the way for new targetable pathways for drug discovery in the context of IPF.