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

描述（由申请人提供）：肺持续暴露于吸入的有毒物质，这些有毒物质会损害传导气道的上皮细胞。涉及祖细胞耗竭的急性损伤通过激活潜在的组织干细胞来修复。然而，大多数环境伤害是重复性的，并导致持续的伤害和修复周期。目前尚不清楚气道干细胞如何有助于修复重复性损伤。本项目的假设是气道干细胞通过增殖和自我更新对多周期损伤作出反应。在伴有炎症的损伤中，干细胞层次的反应失调。为了检验这一假设，将使用核标记保留来跟踪气道干细胞在几乎没有炎症的重复损伤（祖细胞耗竭）模型中的行为（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层次内细胞的修复能力的假设。为了研究炎症对肺祖细胞的影响，将使用矽肺小鼠模型。硅肺是一种纤维化肺部疾病所造成的长期吸入结晶二氧化硅。二氧化硅暴露迅速导致炎性细胞聚集到终末细支气管和肺泡管，这些区域被认为是干细胞所在的区域。将在目标2中检查二氧化硅存在下干细胞和转运扩增细胞增殖反应的受损情况。最后，将使用TNF α受体敲除小鼠来剖析炎症对硅肺中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导致肺部结疤，最终导致呼吸困难。这项提案研究了二氧化硅粉尘如何损害肺中干细胞治愈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部疾病的新治疗方法。在申请表第2页的底部连续编号。不要使用后缀，如2a，2b。

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.