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：哺乳动物的肺有能力在各种受伤后修复。牙槽 维修是一个动态和协调的过程，肺中的茎/祖细胞经历了分化 进入专门的细胞以修复受损的上皮。最近的研究发现了一个独特的中间体 在茎/祖细胞和这些专门细胞之间过渡期间存在的祖细胞状态； 但是，动态的细胞行为和分子调节景观驱动中间祖细胞 细胞过渡向维修的过渡知之甚少。在这里，我们提出了两个目的，以剖析细胞和 在再生哺乳动物肺中控制肺泡修复的分子机制。首先（目标1）我们 将利用永久性肺成像窗口系统来跟踪出现，现场行为和终端 肺泡修复期间，随着时间的流逝，单个中间祖细胞的分化。第二（目标2）我们将 利用组合的SCRNA-SEQ和SCATAC-SEQ以及先进的动力学分析和机器学习 定义细胞状态空间（基因表达和染色质访问性）的技术，细胞轨迹 和过渡中间祖细胞的调节景观。我们将使用 免费体内肺损伤模型和荧光报告小鼠，以跟踪机制 中间祖细胞独有的，可能取决于其细胞起源和/或损伤环境。 该项目将生成广泛的高质量数据集，以实现关键的定量和预测模型 哺乳动物在体内驱动肺泡修复的调节机制。鉴于许多细胞和 肺生物学的分子机制在小鼠和人之间是保守的，我们的发现具有潜力 发现在人类疾病的背景下调节肺泡修复的假定靶标。