Mechanisms Controlling Expansion and Lineage Specification of Airway Progenitors in Development and Disease

摘要 终末期肺部疾病，如慢性阻塞性肺疾病 慢性阻塞性肺疾病（COPD）和特发性肺纤维化（IPF）是人类的毁灭性疾病， 没有有效的治疗方法。越来越多的证据表明， 维持上皮完整性或从持续损伤中恢复可能反映了 干细胞隔室以产生有效再生反应。组织特异 干细胞对于成体器官的体内平衡和完整性至关重要。气道中 上皮这些功能主要归因于多能p63依赖性 基底细胞然而，这种作用由额外的祖细胞共享，特别是由 大量未定型的p63阴性祖细胞占据副基底层， 在基底和管腔分化细胞之间连接的位置。尺寸的变化或 未定型气道上皮祖细胞（基底层、副基底层细胞）库的功能 通常伴随着微架构组织的破坏， 终末期肺病的增生和化生 尽管最近取得了进展，但在以下方面仍然存在重大知识空白： 气道内源性祖细胞共同代表;它们的起源、多样性和 对发育、再生和疾病状态的可塑性的贡献。这里我们 建议在我们的研究计划中解决这些知识差距：a）研究 分子和细胞事件，控制组织和行为的 气道中的干细胞隔室，和B）研究 这些机制在肺部疾病发病机制中的破坏。结果 这些研究将提供目前该领域缺乏的关于组织如何- 特定的干细胞有助于肺中的正常和疾病过程。

ABSTRACT End-stage lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are devastating human conditions for which there are no effective treatments. There is increasing evidence that the inability to maintain epithelial integrity or recovery from sustained injury likely reflects a failure of the stem cell compartment to mount an effective regenerative response. Tissue-specific stem cells are crucial for homeostasis and integrity of adult organs. In the airway epithelium these functions have been attributed largely to multipotent p63-dependent basal cells. However, this role is shared by additional progenitors, particularly by a sizable population of uncommitted p63-negative progenitors which occupy a parabasal location interfacing both basal and luminal differentiating cells. Changes in the size or function of the pool of uncommitted airway epithelial progenitors (basal, parabasal cells) are often accompanied by disruption of the microarchitectural organization seen in hyperplasias and metaplasias of end-stage lung conditions In spite of recent progress, there are still major gaps of knowledge on what collectively the airway endogenous progenitors represent; their origin, diversity, and contribution to plasticity in development, regeneration and disease states. Here we propose to address these gaps of knowledge in our research program to: a) study the molecular and cellular events that control the organization and behavior of the stem cell compartment in the airways, and b) investigate the impact of the disruption of these mechanisms in pulmonary disease pathogenesis. Results from these studies will provide crucial insights currently lacking in the field about how tissue- specific stem cells contribute to normal and disease processes in the lung.