Epithelial Progenitor Cells in Lung Repair and Regeneration

肺细支气管和肺泡上皮细胞在许多重要的人类疾病中有显著的参与， 与肺泡完整性丧失相关的疾病，包括肺气肿和肺纤维化。的每一个中 在这些条件下，产生新肺泡上皮及其相关血管床的能力将被破坏， 具有巨大的潜在治疗价值，但这种能力仍然超出了当前技术的范围。这 应用是基于更好地理解远端ainA/ay和肺泡上皮细胞的想法， 祖细胞生物学是将定向远端肺重塑或修复领域 走向临床竞技场。为此，该应用程序汇集了具有不同 专业知识，但在上皮祖细胞生物学overiapplng利益，以促进远端的理解， 肺的发育、维护和修复。主要目的是：（1）确定转录 迄今为止未表征的远端气道和肺泡祖细胞的程序，并测试假设， 粘附受体的差异表达是上皮亚型自我组织能力的基础 并促进修复。(2)定义对神经内分泌细胞（PNECS）和肺泡祖细胞的要求 细胞在肺损伤后远端气道和肺泡细胞的维持和重建中的作用。(3)分析 并进一步开发了一种新的单细胞体内肾包膜肺类器官测定法， 成体上皮祖细胞从头产生功能性呼吸单位的能力。重要 为实现这些目标而开发的工具和方法包括将可诱导的CRE活性敲入小鼠的 谱系定义基因组位点，基于流式细胞术的技术来分离和转录分析小鼠 和人类胚胎和成人上皮祖细胞，以及创新的成像技术，允许真实的时间捕捉 肺和肺类器官的稳定图像。我们预计，在完成这些工作后， 研究，我们应该能够调整我们的体内试验对原位移植的细胞单位 能够发育肺部。总体而言，这些研究应提供关键的概念和技术 基础设施的临床翻译祖细胞生物学人类肺部疾病。 相关性（参见说明）; 这项建议汇集了几名在以下领域具有广泛但独特专长的调查人员： 上皮细胞生物学的目标是产生概念生物基础设施，以及 用于从祖细胞来源从头产生远端肺组织的技术。项目应 将新概念转化为肺部疾病的治疗。

The pulmonary bronchiolar and alveolar epithelia are involved prominently in a number of important human diseases associated with loss of alveolar integrity, including emphysema and pulmonary fibrosis. In each of these conditions the capacity to generate new alveolar epithelium, and its associated vascular bed, would be of great potential therapeutic value, but such capacity remains beyond the reach of current technology. This application is predicated on the idea that better understanding of distal ainA/ay and alveolar epithelial cell progenitor biology is a crucial part of any effort to move the field of directed distal lung remodeling or repair toward the clinical arena. Toward that end, this application brings together investigative groups with different expertise but overiapplng interests in epithelial progenitor cell biology to advance the understanding of distal lung development, maintenance, and repair. The major objectives are (1) To define the transcriptional program of heretofore uncharacterized distal airway and alveolar progenitors and test the hypothesis that differential expression of adhesion receptors underiies the capacity of epithelial subtypes to self-organize and promote repair. (2) Define the requirement for neuroendocrine cells (PNECS )and alveolar progenitor cells in maintenance and reconstitution of distal airway and alveolar cells following lung injury. (3) Analyze and further develop a novel, single cell in vivo lung organoid assay in kidney capsules in order to optimize the capacity of adult epithelial progenitor cells to generate functional respiratory units de novo. Important tools and approaches developed to achieve these aims include mice with inducible cre activity knocked into lineage-defining genomic loci, flow cytometry-based techniques to isolate and transcriptionally profile mouse and human embryonic and adult epithelial progenitors, and innovative imaging that allows real time capture of stable images of lung and lung organoids over time. We anticipate that by the completion of these studies we should be able to adapt our in vivo assay toward orthotopic transplantation of cellular units capable of lung development. Overall, these studies should provide crucial conceptual and technological infrastructure for the clinical translation of progenitor cell biology to human lung disease. RELEVANCE (See instructions); This proposal brings together several investigators with overiapplng but distinct expertise in the field of epithelial cell biology with the goal of generating the conceptual biological infrastructure as well as technology for creating distal lung tissue de novo from a source of progenitor cells. The projects should empower translation of new concepts to the treatment of lung diseases.