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：哺乳动物的肺具有在各种损伤后自我修复的能力。牙槽骨 修复是一个动态和协调的过程，肺内的干细胞/祖细胞经历分化。 转化成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 在干细胞/祖细胞和这些特化细胞之间的过渡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格局 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解剖细胞和 在再生哺乳动物肺中控制体内肺泡修复的分子机制。第一(目标1)我们 将利用一个永久性的肺部成像窗口系统来跟踪出现、活着的行为和终端 单个中间祖细胞在牙槽骨修复过程中随时间的分化。第二(目标2)我们将 结合使用scRNA-seq和scatac-seq以及高级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 以及过渡中间祖细胞的调控格局。我们将使用以下工具实现这两个目标 免费的活体肺损伤模型和荧光报告小鼠，以跟踪以下机制 这是中间祖细胞所特有的，并可能依赖于它们的细胞起源和/或损伤背景。 该项目将生成广泛的、高质量的数据集，以实现关键的定量和预测模型 哺乳动物体内驱动肺泡修复的调节机制。考虑到许多细胞和 肺生物学的分子机制在小鼠和人之间是保守的，我们的发现有可能 在人类疾病的背景下，揭示调节肺泡修复的假定靶点。