Stem Cells to Enhance Bronchiolar Reparative Capacity.

描述（由申请人提供）：本提案的目标是扩展肺干细胞生物学的基本原理，以开发有效的策略来扩增和纯化肺干细胞，将其输送到修复缺陷气道，并增强上皮修复能力。该建议的基本前提是，上皮细胞修复能力的缺陷是导致慢性肺部疾病进展的一个共同因素，旨在增强上皮细胞修复能力的策略将是影响肺再生治疗的重要组成部分。为了实现这一提议的目标，我们组织了一个研究团队，从干细胞生物学、细胞治疗、肺损伤和修复以及人类慢性肺部疾病的临床管理方面的专业知识的基础和临床科学家。本申请中提出的研究的科学基础是基于我们之前的证明，即维持上皮修复能力需要内源性组织干细胞，并且小鼠气道中b-catenin信号的增强导致具有内在修复能力的内源性干细胞的扩增。因此，我们假设能够瞬时激活b-catenin信号传导的药物干预将导致内源性干细胞的扩增和上皮修复能力的增强，并且通过增强b-catenin信号传导获得的丰富的修复细胞群可用于修复缺陷受体气道上皮修复能力的恢复。提出了三个目标，将建立一个平台，在此基础上，细胞疗法可以进一步发展。目的1将利用b-连环蛋白信号的瞬时激活来扩增小鼠和人气道干细胞。在Aim 2中，我们将定义细支气管干细胞的细胞表面表型，用于气道干细胞的纯化和富集。最后，在Aim 3中，我们将测试使用扩增细支气管干细胞恢复修复缺陷气道修复能力的可行性。实现这些目标将为进一步开发肺组织修复细胞修复策略提供合理的基础。

DESCRIPTION (provided by applicant): 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 b-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 b-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 b-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.