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)是人类对 目前还没有有效的治疗方法。越来越多的证据表明，无法 保持上皮完整性或从持续损伤中恢复可能反映了 干细胞室，以建立有效的再生反应。组织特异性 干细胞对成年器官的动态平衡和完整性至关重要。在呼吸道里 上皮细胞的这些功能在很大程度上归因于多潜能p63依赖 基底细胞。然而，这一角色由其他祖先共享，特别是由 相当大数量的未承诺的p63阴性祖细胞，占据副基细胞 连接基底和腔内分化细胞的位置。大小或尺寸的变化 未定植的呼吸道上皮祖细胞池(基底细胞、旁基底细胞)的功能 通常伴随着微体系结构组织的中断，如 终末期肺部疾病的增生性和化生性 尽管最近取得了进展，但在哪些方面仍存在重大认识差距 呼吸道内源性前体细胞共同代表；它们的起源、多样性和 在发育、再生和疾病状态下对可塑性的贡献。在这里我们 建议在我们的研究计划中解决这些知识差距：a)研究 控制组织和行为的分子和细胞事件 在呼吸道中的干细胞隔间，以及b)调查 这些机制在肺部疾病发病机制中的干扰。结果来自 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部的正常和疾病过程。

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.