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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要包括特发性肺纤维化 (IPF) 在内的间质性肺疾病 (ILD) 与显着相关发病率和死亡率。 ILD 患者的治疗选择因缺乏对 ILD 的了解而受到限制。病理生理机制。肺泡 2 型 (AT2) 细胞是肺泡中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的产生并作为干细胞祖细胞通过生成肺泡 1 型 (AT1) 细胞来修复损伤后的肺泡。干扰 DNA、蛋白质、细胞器质量控制和细胞代谢都被假设为 AT2 细胞的基础驱动ILD。最近对 AT2 细胞状态和分化轨迹的见解导致了引发的发现和循环 AT2（pAT2 和 cAT2）细胞亚群和肺泡分化中间（ADI）细胞，在肺损伤期间转化为 AT1 细胞。然而，全球监管机制有助于 AT2 细胞稳态失调以及与 AT2 祖细胞更新受损的关系并不存在很好理解。在前期工作中，我们发现let-7 microRNA簇的条件失活特异性小鼠肺泡 AT2 细胞促进自发的年龄依赖性实质重塑，其特征为 ILD 包括明显的间隔肺泡增厚、具有胶原沉积的成纤维细胞病灶以及明显的肺泡炎。我们还发现let-7促进AT2细胞增生和ADI移行细胞的出现具有细胞衰老特征的细胞。基于转录组数据假设 let-7 家族 microRNA 作为 AT2 细胞自噬和脂质稳态、祖干细胞的重要协调者更新和 AT1 分化。在本提案中，我们将扩展这些令人兴奋的发现以（1）确定如何 let-7 通路在 ILD 期间调节 AT2 祖干细胞轨迹和细胞分化动态； (2) 确定 let-7 通路如何损害 AT2 细胞表面活性剂稳态并导致自噬的改变 ILD 重塑过程中的脂质代谢； (3) 确定let-7控制AT2细胞的机制老鼠和人类的更新。该项目将阐明基本的修复和再生过程肺，并为 IPF 背景下药物发现的新靶向途径铺平道路。