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

描述let-7 microRNA对肺AT2细胞稳态、肺泡再生和间质性肺疾病的作用

• 批准号: 10634881
• 负责人: Antony Rodriguez
• 金额: $ 52.55万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634881
• 关键词: AT-Hook Motifs; ATAC-seq; Aging; Alveolar; Alveolitis; Alveolus; Animal Model; Apoptosis; Appearance; Architecture; Autophagocytosis; Bioenergetics; Biological Assay; Bleomycin; Cell Aging; Cell Compartmentation; Cell Differentiation process; Cell Survival; Cell physiology; Cells; Cellular Metabolic Process; Characteristics; Chronic lung disease; Collagen; Complex; DNA; Data; Defect; Deposition; Development; Enhancers; Ensure; Epithelium; Experimental Genetics; Family; Felis catus; Fibrosis; Functional disorder; Generations; Genes; Genetic; Genus Hippocampus; Goals; Homeostasis; Human; Hyperplasia; Hypoxemia; Immune; Immunofluorescence Immunologic; Impairment; Inflammation; Injury; Interstitial Lung Diseases; Knockout Mice; Knowledge; Lipids; Lung; Lung fibrogenesis; Measurement; Metabolic; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Nodal; Organelles; Pathogenicity; Pathway interactions; Patients; Physiological; Play; Pluripotent Stem Cells; Polycomb; Process; Proliferating; Proteins; Proto-Oncogene Proteins c-myc; Public Health; Pulmonary Emphysema; Pulmonary Fibrosis; Pulmonary Surfactants; Quality Control; Regulation; Repression; Research; Resolution; Role; Somatic Cell; Stress; System; Testing; Time; Tissue Model; Tomatoes; Tracer; Transitional Cell; Upstream Enhancer; Work; age related; alveolar lamellar body; cell growth; disease diagnosis; drug discovery; effective therapy; healing; human tissue; idiopathic pulmonary fibrosis; improved; in vivo; insight; lipid metabolism; lung injury; mortality; mouse model; novel therapeutics; prevent; progenitor; programs; repaired; response; senescence; stem; stem cell division; stem cell fate; stem cell population; stem cells; surfactant; surfactant production; tissue repair; transcription factor; transcriptomics; transdifferentiation

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.

项目摘要 包括特发性肺纤维化（IPF）在内的间质肺疾病（ILD）与显着相关 发病率和死亡率。 ILD患者的治疗选择受到对 病理生理机制。肺泡2型（AT2）细胞，主要上皮祖细胞中的主要上皮祖细胞种群 肺在ILD病理生理学中至关重要，因为它们调节表面活性剂的产生并起作用 通过产生1型肺泡1（AT1）细胞，用于修复肺泡后修复肺泡的干细胞祖细胞。干扰 DNA，蛋白质，细胞器质量控制和细胞代谢都被认为是AT2细胞的基础 驱动的ILD。对AT2细胞状态和分化轨迹的最新见解导致发现了底漆 和循环AT2（PAT2和CAT2）细胞亚群（S）和肺泡分化中间体（ADI）细胞， 在肺损伤期间转化为AT1细胞。但是，有助于的全球监管机制 AT2细胞稳态失调以及AT2祖细胞更新的关系不足 理解。在初步工作中，我们发现特定的let-7 microRNA簇的条件失活 在小鼠的肺泡AT2细胞中，促进自发年龄依赖性实质重塑 ILD包括明显的肺泡增厚，胶原蛋白沉积的成纤维细胞灶并发音 肺泡炎。我们还发现，Let-7促进了AT2细胞的增生和ADI过渡的出现 具有细胞衰老谱的细胞。基于转录组数据，假设的let-7家族 MicroRNA是AT2细胞自噬和脂质稳态，祖细胞的必不可少的协调员 续订和AT1分化。在此提案中，我们将把这些令人兴奋的发现扩展到（1）确定 Let-7途径调节ILD期间AT2祖细胞细胞轨迹和细胞分化动力学。 （2） 确定Let-7途径如何损害AT2细胞表面活性剂稳态，并有助于自噬的改变 和ILD重塑期间的脂质代谢； （3）确定Let-7控制AT2细胞的机制 在老鼠和人类中更新。该项目将阐明基本维修和再生过程 在IPF的背景下，肺和为新目标途径铺平了道路。