Epithelial Progenitor Cells in Lung Repair and Regeneration

肺细管上皮和肺泡上皮在许多重要的人类疾病中有显著的受累。 与肺泡完整性丧失有关的疾病，包括肺气肿和肺纤维化。在每一个中 在这些条件下，产生新的肺泡上皮及其相关的血管床的能力将是 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能力。这 应用的基础是更好地理解远端肺泡上皮细胞和肺泡上皮细胞 祖细胞生物学是任何推动定向远端肺重塑或修复领域的努力的关键部分。 向临床领域进军。为此，这个应用程序将不同的调查小组聚集在一起 在上皮祖细胞生物学方面的专业知识但超过兴趣，以促进对远端的理解 肺的发育、维护和修复。主要目标是(1)定义转录 迄今尚未特化的远端气道和肺泡祖细胞的程序，并检验假设 黏附受体的差异表达与上皮亚型的自组织能力有关 并促进修复。(2)明确神经内分泌细胞(PNECs)和肺泡祖细胞的要求 细胞与肺损伤后远端呼吸道和肺泡细胞的维持和重建。(3)分析 并进一步发展了一种新颖的、单细胞活体肺组织类物质肾胶囊的检测方法，以优化 成体上皮祖细胞从头产生功能呼吸单位的能力。重要 为实现这些目标而开发的工具和方法包括具有可诱导的cre活性的小鼠。 基于流式细胞术的谱系定义基因组基因座分离和转录图谱分析技术 以及人类胚胎和成人上皮祖细胞，以及允许实时捕获的创新成像 肺和肺器官随时间变化的稳定图像。我们预计在这些项目完成后， 我们应该能够使我们的体内检测方法适用于细胞单位的原位移植 有肺发育能力的。总体而言，这些研究应提供至关重要的概念和技术 将祖细胞生物学临床转化为人类肺部疾病的基础设施。 相关性(见说明)； 这项建议汇集了几位在这一领域具有卓越但独特专长的调查人员 上皮细胞生物学，目标是产生概念性的生物基础设施以及 从祖细胞来源创造远端肺组织的技术。这些项目应该 将新概念转化为肺部疾病的治疗方法。

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.