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

项目摘要 包括特发性肺纤维化（IPF）在内的间质性肺疾病（ILD）与显著的 发病率和死亡率。ILD患者的治疗选择因缺乏对 病理生理机制肺泡2型（AT 2）细胞，主要的上皮祖干细胞群， 肺在ILD病理生理学中至关重要，因为它们调节表面活性剂产生， 干细胞祖细胞用于通过产生肺泡1型（AT 1）细胞在损伤后修复肺泡。中断 DNA、蛋白质、细胞器质量控制和细胞代谢都被假设为AT 2-细胞基础 驱动ILD。最近对AT 2细胞状态和分化轨迹的了解导致了启动子的发现。 以及循环AT 2（pAT 2和cAT 2）细胞亚群和肺泡分化中间（ADI）细胞， 在肺损伤时转化为AT 1细胞。然而，有助于实现这一目标的全球监管机制 AT 2细胞稳态失调和与AT 2祖细胞更新受损的关系并不 很好理解。在初步工作中，我们发现let-7 microRNA簇的条件失活特异性地 在小鼠肺泡AT 2细胞中促进自发的年龄依赖性实质重塑， ILD包括明显的间隔肺泡增厚、成纤维细胞灶伴胶原沉积和明显的 肺泡炎我们还发现let-7促进AT 2细胞的增生和ADI过渡型的出现。 具有细胞衰老特征的细胞。基于转录组学数据，假设let-7家族的转录水平与转录水平相关。 microRNA是AT 2细胞自噬和脂质稳态、祖细胞干细胞和细胞外基质的重要协调者。 更新和AT 1分化。在本提案中，我们将把这些令人兴奋的发现扩展到（1）确定 let-7通路调节ILD期间AT 2祖干细胞轨迹和细胞分化动力学;（2） 确定let-7通路如何损害AT 2细胞表面活性剂的稳态，并有助于自噬的改变 以及（3）确定let-7控制AT 2细胞的机制 在小鼠和人类中的更新。该项目将阐明一个基本的修复和再生过程中， 并为IPF背景下的新靶向药物发现途径铺平道路。

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.