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

项目摘要 间质性肺疾病(ILDS)，包括特发性肺纤维化(IPF)，与显著 发病率和死亡率。ILD患者的治疗选择受到缺乏对 病理生理机制。肺泡2型(AT2)细胞是人类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物质的产生并作为 用于通过产生肺泡1型(AT1)细胞修复损伤后肺泡的干细胞前体细胞。中断到 DNA、蛋白质、细胞器质量控制和细胞代谢都被假设为2-细胞的基础 驾驶ILD。对AT2细胞状态和分化轨迹的最新见解导致了Primed的发现 和周期AT2(pAT2和cAT2)细胞亚群(S)和肺泡分化中间细胞(ADI)， 在肺损伤过程中转化为AT1细胞。然而，全球监管机制有助于 AT2细胞稳态失调及其与AT2祖细胞干细胞更新受损的关系 很好理解。在初步工作中，我们发现let-7 microRNA的条件性失活具有特异性 小鼠肺泡AT2细胞促进自发的年龄依赖性实质重塑，其特征是 ILD包括明显的肺泡间隔增厚，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促进了AT2细胞的增殖和ADI移行细胞的出现 具有细胞衰老特征的细胞。根据转录数据假设，let-7家族 MicroRNAs是AT2细胞自噬和脂类稳态、祖细胞干细胞的重要协调者 更新和AT1分化。在这项提案中，我们将把这些令人兴奋的发现扩展到(1)确定 LET-7通路在ILD中对AT2前体干细胞轨迹和细胞分化动力学的调控；(2) 确定let-7通路如何破坏AT2细胞表面活性物质的动态平衡并促进自噬的改变 和脂代谢在ILD重塑中的作用；(3)确定let-7调控AT2细胞的机制(S)。 小鼠和人类的更新。该项目将阐明一个基本的修复和再生过程在 此外，我们还将继续努力，并为在森林小组框架内发现药物的新的目标路径铺平道路。

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.