A Promitotic Stem Cell Niche: Role For Beta-Catenin and TGFbeta

描述（由申请人提供）： 概述：本研究的目的是确定调控气管支气管上皮组织特异性干细胞（TSC）及其微生态位之间相互作用的细胞和分子机制。TSC自我更新和分化程序的失调已经被认为是许多上呼吸道疾病如COPD、哮喘和CF的原因。 我的初步数据表明，小鼠气管TSCs产生自己的生态位，这是促有丝分裂的性质和修改这个生态位是必要的分化。这种修饰是通过来自分化的气管细胞的环境线索来完成的。基于这些初步数据，我将确定1）这些TSCs在组织修复中的作用，以及2）参与维持增殖生态位的信号通路。 研究的意义：本研究将通过解决2个基本范例来推进肺TSC领域：1）TSC参与受损上皮的修复，以及2）允许转运放大细胞（TAC）分化的信号传导途径。最后，这项研究提供了一个重要的修改“种子和土壤”的范例为基础的细胞治疗的可能性，引入纯干细胞/小生境细胞受伤的器官可能会导致不受限制的扩张的有丝分裂队列由于疾病相关的消耗的分化细胞修改的小生境。 创新：rim-clone测定的开发允许从单个TSC产生大量TAC（8x10^3）。该方法将允许通过细胞混合研究和使用药理学方法使用来自遗传修饰小鼠的TSC分析信号传导机制。因此，我将有能力在受控条件下首次评估TSC增殖和分化。

DESCRIPTION (provided by applicant): Overview: The goal of this proposal is to identify the cellular and molecular mechanisms that regulate interactions between the tracheobronchial epithelial tissue-specific stem cell (TSC) and its niche. Dysregulation of the TSC self-renewal and differentiation program has been suggested for many upper airway diseases like COPD, asthma, and CF. My preliminary data indicate that mouse tracheal TSCs generate their own niche that is promitotic in nature and modification of this niche is necessary for differentiation. This modification is accomplished by environmental cues derived from differentiated tracheal cells. Based on this preliminary data, I will determine 1) the role of these TSCs in tissue repair, and 2) the signaling pathways involved in maintenance of the proliferative niche. Significance of the study: This study will advance the field of lung TSC by addressing 2 fundamental paradigms: 1) TSC participation in repair of the damaged epithelium, and 2) signaling pathways that allow differentiation of transit amplifying cells (TAC). Finally, this study provides an important modification of the "seed and soil" paradigm for cell-based therapy by raising the possibility that introduction of pure stem/niche cells to an injured organ may result in unrestrained expansion of the mitotic cohort due to disease-associated depletion of the differentiated cells that modify the niche. Innovation: Development of a rim-clone assay allows generation of large number of TAC (8x10^3) from a single TSC. This method will permit analysis of signaling mechanisms using TSC from genetically-modified mice, through cell-mixing studies and using pharmacological approaches. Thus, I will have the ability to evaluate TSC proliferation and differentiation under controlled conditions for the first time.