Regulation of Progenitor Cell Plasticity in Lung Development and Disease-Repair

肺发育和疾病修复中祖细胞可塑性的调节

• 批准号: 10574208
• 负责人: Wellington V. Cardoso
• 金额: $ 111.79万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2030-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574208
• 关键词: Address; Adult; Alveolus; Behavior; Biology; Cell Compartmentation; Cells; Chronic Disease; Chronic Obstructive Pulmonary Disease; Development; Disease; Epithelium; Future; Genetic Models; Growth; Human; Knowledge; Link; Lung; Lung diseases; Natural regeneration; Organoids; Perinatal; Process; Pulmonology; Regulation; Research Proposals; Resolution; Technology; Therapeutic Intervention; cohort; epidemiologic data; fetal; genetic epidemiology; human disease; insight; intrauterine environment; lung development; lung injury; lung repair; mouse genetics; mouse model; neonatal human; prevent; progenitor; programs; repaired; stem cells

ABSTRACT Despite much progress in the field of lung biology and pulmonary medicine, a major gap of knowledge remains in the lack of a broader understanding of the composition and regulation of the lung stem cell compartment and its behavior in disease and regeneration-repair. Recent studies bring an additional complexity to the scenario, as they describe injured lung cells in a plastic intermediate state at the crossroad between resolution to a normal state and abnormal failed repair of the lung. Little is known about the origin and regulation of these intermediate cell states and their relationship to the programs that regulate cell fate decisions in the developing lung. There has been also an increasing need to have a better understanding of the developmental and repair programs in human lung progenitors, their impact in perinatal conditions and potential link to adult chronic diseases. Here we propose to address these gaps of knowledge in this research proposal by: a) exploring new observations that identify a similar transitional state in developing lung epithelial progenitors, to investigate mechanisms of cell plasticity that balances the cell fate program of airways and alveoli and prevents aberrant lung growth, b) investigating the developmental origins of dysanaptic lung growth and its link to COPD by integrating information from genetic-epidemiologic cohorts with that from organoid and mouse genetic models, c) investigating the impact of fetal–intrauterine environment in the control of plasticity and maturation of human neonatal airway progenitor cells. Results from these studies will open new perspectives in our understanding of the mechanisms of how cell fate decisions are regulated in development and disease- repair providing insights for future therapeutic interventions.

摘要 尽管在肺生物学和肺医学领域取得了很大进展，但知识的主要差距 仍然缺乏对肺干细胞的组成和调节的更广泛的理解， 室及其在疾病和再生修复中的行为。最近的研究显示， 复杂的情况下，因为他们描述了受伤的肺细胞在一个塑料中间状态， 恢复正常状态和肺修复异常失败之间的交叉点。知之甚少 关于这些中间细胞状态的起源和调节以及它们与程序的关系， 在发育中的肺中调节细胞命运的决定。也越来越需要有 更好地了解人类肺祖细胞的发育和修复程序， 对围产期状况影响以及与成人慢性病的潜在联系。在这里，我们建议解决 这些知识的差距，在这项研究建议：a）探索新的观察，确定一个 在发育中的肺上皮祖细胞中存在类似的过渡状态，以研究细胞 平衡气道和肺泡的细胞命运程序并防止异常肺生长的可塑性， B）通过整合呼吸系统疾病和慢性阻塞性肺疾病，研究适应不良肺生长的发育起源及其与COPD的联系。 来自遗传流行病学队列的信息与来自类器官和小鼠遗传模型的信息，c） 研究胎儿宫内环境在控制胚胎发育的可塑性和成熟中的影响， 人新生儿气道祖细胞这些研究的结果将为我们的研究开辟新的视角。 了解细胞命运决定在发育和疾病中的调节机制- 修复为未来的治疗干预提供见解。