Defining the cellular dynamics that orchestrate alveolar epithelial cell repair behaviors in live mammal

定义协调活体哺乳动物肺泡上皮细胞修复行为的细胞动力学

• 批准号: 10556676
• 负责人: Maurizio Chioccioli
• 金额: $ 43.64万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556676
• 关键词: AGTR2 gene; Affect; Alveolar; Behavior; Biology; Cell Differentiation process; Cells; Chromatin; Clinical; Code; Data; Data Set; Distal; Epithelial Cells; Epithelium; Exhibits; Gene Expression; Heterogeneity; Human; Image; Individual; Injury; Label; Lung; Lung diseases; Machine Learning; Mammals; Modeling; Molecular; Molecular Profiling; Molecular Target; Mus; Nucleic Acid Regulatory Sequences; Outcome; Pathway interactions; Population; Process; Reporting; Resolution; Source; Specific qualifier value; System; Techniques; Testing; Therapeutic Intervention; Time; Work; alveolar epithelium; cell behavior; cell type; cellular targeting; combinatorial; gene regulatory network; human disease; imaging system; in vivo; in vivo regeneration; injured; lung imaging; lung injury; lung repair; multiple omics; novel; predictive modeling; progenitor; repaired; single-cell RNA sequencing; spatiotemporal; stem; stem cells; transcription factor

PROJECT SUMMARY: The mammalian lung has the capacity to repair itself following various injuries. Alveolar repair is a dynamic and coordinated process whereby stem/progenitor cells in the lung undergo differentiation into specialized cells to repair the damaged epithelium. Recent studies have uncovered a distinct intermediate progenitor cell state that exists during the transition between stem/progenitor cells and these specialized cells; however, the dynamic cellular behaviors and molecular regulatory landscape that drives intermediate progenitor cell transitions toward repair is poorly understood. Here, we propose two aims to dissect the cellular and molecular mechanisms that control alveolar repair in vivo in the regenerating mammalian lung. First (Aim 1) we will utilize a permanent lung imaging window system to track the emergence, live behaviors and terminal differentiation of individual intermediate progenitor cells over time during alveolar repair. Second (Aim 2) we will utilize combined scRNA-seq and scATAC-seq together with advanced dynamical analysis and machine learning techniques to define the cellular state space (gene expression and chromatin accessibility), cellular trajectories and regulatory landscape of transitioning intermediate progenitor cells. We will perform both aims using complimentary in vivo lung injury models and fluorescent report mice in order to track the mechanisms that are unique to intermediate progenitor cells and potentially dependent on their cellular origin and/or injury context. This project will generate extensive, high quality datasets to enable quantitative and predictive models of the key regulatory mechanisms that mammalian drive alveolar repair in vivo. Given that many of the cellular and molecular mechanisms of lung biology are conserved between mouse and human, our findings have the potential to uncover putative targets for modulating alveolar repair in the context of human disease.

项目摘要：哺乳动物的肺部在各种损伤后具有自我修复的能力。肺泡 修复是一个动态且协调的过程，肺中的干细胞/祖细胞在此过程中进行分化 进入专门的细胞来修复受损的上皮。最近的研究发现了一种独特的中间体 干细胞/祖细胞与这些特化细胞之间转变过程中存在的祖细胞状态； 然而，驱动中间祖细胞的动态细胞行为和分子调控景观 人们对细胞向修复的转变知之甚少。在这里，我们提出了两个目标来剖析细胞和 控制再生哺乳动物肺体内肺泡修复的分子机制。首先（目标 1）我们 将利用永久性肺部成像窗口系统来跟踪出现情况、实时行为和终端 肺泡修复过程中各个中间祖细胞随着时间的推移而分化。第二（目标 2）我们将 利用组合的 scRNA-seq 和 scATAC-seq 以及先进的动态分析和机器学习 定义细胞状态空间（基因表达和染色质可及性）、细胞轨迹的技术 和过渡中间祖细胞的调控景观。我们将使用以下方法实现这两个目标 互补的体内肺损伤模型和荧光报告小鼠，以追踪肺损伤的机制 对于中间祖细胞来说是独特的，并且可能取决于它们的细胞起源和/或损伤背景。 该项目将生成广泛的高质量数据集，以实现关键关键因素的定量和预测模型 哺乳动物体内驱动肺泡修复的调节机制。鉴于许多蜂窝和 肺生物学的分子机制在小鼠和人类之间是保守的，我们的发现具有潜力 发现在人类疾病背景下调节肺泡修复的假定目标。