Regulation of the Airway Stem Cell Compartment in Airway Repair and Remodeling

描述（由申请人提供）：肺部经常暴露于吸入的有毒物质中，这些有毒物质会损害导气管的上皮细胞。涉及祖细胞耗竭的急性损伤可通过激活潜伏组织干细胞来修复。然而，大多数环境伤害是重复性的，导致损伤和修复的持续循环。目前尚不清楚气道干细胞如何修复重复性损伤。这个项目的假设是气道干细胞通过增殖和自我更新来应对多个周期的损伤。在伴随炎症的损伤中，干细胞层级的反应失调。为了验证这一假设，将使用核标签保留来跟踪气道干细胞在重复性损伤（祖细胞耗竭）模型中的行为，这种模型发生在很少的炎症中（Aim i）。第二个和第三个目标将研究与持续炎症相关的损伤影响细支气管干细胞等级内细胞修复能力的假设。为了研究炎症对肺祖细胞的影响，我们将采用小鼠矽肺模型。矽肺病是一种因长期吸入结晶二氧化硅而引起的纤维化肺病。二氧化硅暴露迅速导致炎性细胞聚集到末梢细支气管和肺泡管，这些区域被认为是干细胞的所在地。干细胞和转运扩增细胞在二氧化硅存在下增殖反应的损伤将在Aim 2中进行检查。最后，将使用TNFa受体敲除小鼠来解剖炎症对矽肺病细支气管上皮再生能力受损的贡献（目的3）。这些研究的最终目标是确定矽肺病如何损害干细胞层次结构，并确定可能阻止疾病进展的治疗靶点。吸入二氧化硅粉尘会在肺部留下疤痕，最终导致呼吸困难。本提案研究二氧化硅粉尘如何损害肺干细胞愈合肺损伤而不留下疤痕的能力。从这项研究中获得的信息可能有助于确定慢性肺病的新治疗方法。在申请表第二页的底部连续编号。不要使用诸如2a、2b之类的后缀。

DESCRIPTION (provided by applicant): The lung is constantly exposed to inhaled toxicants that damage the epithelial cells of the conducting airway. Acute injuries involving depletion of progenitor cells are repaired through activation of latent tissue stem cells. However, most environmental injuries are repetitive and result in continual cycles of injury and repair. It is unknown how airway stem cells contribute to repairing repetitive injuries. The hypothesis of this project is that airway stem cells respond to multiple cycles of injury by both proliferating and self-renewing. In injuries accompanied by inflammation, the response of the stem cell hierarchy is dysregulated. To test this hypothesis, nuclear label retention will be used to follow the behavior of airway stem cells in a model of repetitive injury (progenitor cell depletion) that occurs with little inflammation (Aim i). The second and third aims will investigate the hypothesis that injury associated with sustained inflammation impacts the reparative capacity of cells within the bronchiolar stem cell hierarchy. To study the effects of inflammation on lung progenitor cells, a mouse model of silicosis will be used. Silicosis is a fibrotic lung disease caused by long-term inhalation of crystalline silica. Silica exposure rapidly causes inflammatory cell recruitment to the terminal bronchioles and alveolar ducts, regions where stem cells are thought to reside. Impairment of the proliferate responses of the stem cells and transit amplifying cells in the presence of silica will be examined in Aim 2. Finally, TNFa receptor knockout mice will be used to dissect the contribution of inflammation to the impaired regenerative ability of the bronchiolar epithelium in silicosis (Aim 3). The eventual goals of these studies are to determine how silicosis impairs the stem cell hierarchy and to identify therapeutic targets that may halt disease progression. Inhaling silica dust causes scarring in the lung that eventually makes it difficult to breathe. This proposal studies how silica dust impairs the ability of stem cells in the lung to heal lung injuries without scarring. The information learned from this research may help identify new treatments for chronic lung disease. Number pages consecutively at the bottom throughout Form Page 2 the application. Do not use suffixes such as 2a, 2b.