Stem Cells to Enhance Bronchiolar Reparative Capacity.

这项建议的目标是扩展肺干细胞生物学的基本原理，以发展 扩增和纯化肺干细胞的有效策略，将它们输送到修复缺陷的呼吸道，以及 增强上皮修复能力。这项提议所基于的基本前提是 上皮细胞修复能力的缺陷是导致 慢性肺部疾病的进展，旨在增强上皮修复能力的战略将 是影响肺再生的治疗的重要组成部分。为了实现这项提案的目标，我们 组织了一个研究小组，由具有干细胞生物学专业知识的基础和临床科学家组成， 以细胞为基础的治疗，肺损伤和修复，以及人类慢性肺部疾病的临床管理。 本申请中提出的研究的科学基础是基于我们之前的演示 内源性组织干细胞是维持上皮修复能力所必需的，而且 P-连环蛋白信号在小鼠呼吸道中的增强导致内源性干细胞的扩张， 港湾固有的修复能力。因此，我们假设药物干预能够 瞬时激活p-catenin信号会导致内源性干细胞的扩增和增强 上皮修复能力，以及通过增强获得的丰富的修复细胞群 P-连环蛋白信号转导可用于修复缺陷受体上皮修复能力的恢复 航空公司。提出了三个目标，将建立一个基于细胞的治疗可以进一步发展的平台 发展起来的。目标1将利用b-连环蛋白信号的瞬时激活来扩增小鼠和 人类呼吸道干细胞。在目标2中，我们将定义细支气管干细胞的细胞表面表型 预期对呼吸道干细胞进行纯化和浓缩。最后，在目标3中，我们将测试 利用扩增的细支气管干细胞恢复修复缺陷的呼吸道的修复能力。 实现这些目标将提供合理的基础，在此基础上进一步制定 将修复细胞输送到肺组织以矫正上皮修复缺陷。

Goals of this proposal are to extend fundamental principles in lung stem cell biology for the development of effective strategies to amplify and purify lung stem cells, deliver them to repair deficient airways, and enhance epithelial reparative capacity. The underlying premise upon which this proposal is based is that defects in the reparative capacity of epithelial cells represent a common factor contributing to the progression of chronic lung disease, and that strategies aimed at enhancing epithelial reparative capacity will be essential components of treatments to effect lung regeneration. To achieve the goals of this proposal we have organized a research team drawing from basic and clinical scientists with expertise in stem cell biology, cell-based therapy, lung injury and repair, and the clinical management of chronic lung disease in humans. The scientific foundation for studies proposed in this application is based upon our previous demonstration that endogenous tissue stem cells are required for maintenance of epithelial reparative capacity, and that potentiation of p-catenin signaling in airways of mice leads to expansion of endogenous stem cells that harbor intrinsic reparative capacity. Accordingly, we hypothesize that pharmacologic interventions capable of transiently activating p-catenin signaling will lead to expansion of endogenous stem cells and enhanced epithelial reparative capacity, and that enriched populations of reparative cells obtained through potentiation of p-catenin signaling can be used for restoration of epithelial reparative capacity in repair-deficient recipient airways. Three aims are proposed that will build a platform upon which cell-based therapies can be further developed. Aim 1 will use transient activation of b-catenin signaling for the amplification of mouse and human airway stem cells. In Aim 2, we will define the cell surface phenotype of bronchiolar stem cells for the prospective purification and enrichment of airway stem cells. Finally, in Aim 3, we will test the feasibility of using amplified bronchiolar stem cells for the restoration of reparative capacity in repair-deficient airways. Accomplishing these aims will provide a rational foundation upon which to further develop strategies for the delivery of reparative cells to lung tissue for correction of epithelial repair defects.