Stem Cells to Enhance Bronchiolar Reparative Capacity.

描述(申请人提供)：这项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，将它们输送到修复缺陷的呼吸道，并增强上皮修复能力。这一建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进展的共同因素，旨在增强上皮修复能力的策略将是实现肺再生的治疗的基本组成部分。为了实现这项建议的目标，我们组织了一个研究小组，成员来自基础和临床科学家，他们在干细胞生物学、基于细胞的治疗、肺损伤和修复以及人类慢性肺部疾病的临床管理方面具有专业知识。在这项申请中提出的研究的科学基础是基于我们之前的论证，即内源性组织干细胞是维持上皮修复能力所必需的，并且小鼠呼吸道中b-连环蛋白信号的增强导致具有内在修复能力的内源干细胞的扩张。因此，我们假设，能够瞬时激活b-catenin信号的药物干预将导致内源性干细胞的扩张和上皮修复能力的增强，并且通过增强b-catenin信号获得的丰富的修复细胞群可用于修复修复缺陷的受体呼吸道的上皮修复能力。提出了三个目标，将建立一个平台，在此平台上可以进一步发展基于细胞的疗法。目标1将使用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，我们将确定细支气管干细胞的细胞表面表型，为未来的呼吸道干细胞的纯化和浓缩奠定基础。最后，在目标3中，我们将测试使用扩增的细支气管干细胞来恢复修复缺陷的呼吸道修复能力的可行性。实现这些目标将提供一个合理的基础，在此基础上进一步制定策略，将修复细胞输送到肺组织，以纠正上皮修复缺陷。

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.