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

气道干细胞室在气道修复和重塑中的调节

• 批准号: 7483716
• 负责人: Anna Christine Zemke
• 金额: $ 4.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483716
• 关键词: Acute; Alveolar Duct; Asthma; Behavior; Breathing; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Chronic; Chronic lung disease; Cicatrix; Clara cell; Cystic Fibrosis; Disease; Disease Progression; Duct (organ) structure; Dust; Epithelial; Epithelial Cells; Epithelium; Experimental Models; Goals; Healed; Homeostasis; Impairment; Inflammation; Inflammatory; Injury; Knockout Mice; Label; Laboratories; Learning; Lung; Lung Inflammation; Lung diseases; Mediating; Modeling; Mus; Naphthalene; Naphthalenes; Natural regeneration; Neuroepithelial Bodies; Nuclear; Numbers; Population; Proliferating; Regulation; Research; Signal Transduction; Silicon Dioxide; Silicosis; Stem cells; Stimulus; Terminal Bronchiole; Testing; Thinking; Tissues; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Wound Healing; airway remodeling; body system; concept; healing; human TNF protein; in vivo; injury and repair; lung injury; mouse model; novel therapeutics; prevent; progenitor; receptor; repaired; response; therapeutic target; toxicant

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.

描述(申请人提供)：肺部经常暴露在吸入的毒物中，这些毒物破坏了传导呼吸道的上皮细胞。包括祖细胞耗尽的急性损伤通过激活潜伏的组织干细胞来修复。然而，大多数环境损伤是重复的，导致损伤和修复的连续循环。目前尚不清楚呼吸道干细胞如何在修复反复损伤中发挥作用。该项目的假设是，呼吸道干细胞通过增殖和自我更新对多个周期的损伤做出反应。在伴有炎症的损伤中，干细胞层次的反应是失调的。为了验证这一假说，核标记保留将用于跟踪呼吸道干细胞在重复性损伤(祖细胞耗竭)模型中的行为，该模型发生在几乎没有炎症的情况下(Aim I)。第二个和第三个目标将调查与持续炎症相关的损伤影响细支气管干细胞层次内细胞修复能力的假设。为了研究炎症对肺祖细胞的影响，将使用矽肺的小鼠模型。矽肺是一种长期吸入结晶二氧化硅引起的纤维性肺部疾病。接触二氧化硅会迅速导致炎症细胞重新聚集到终末细支气管和肺泡管，这两个区域被认为是干细胞的居住地。在Aim 2中将检测在二氧化硅存在下干细胞和过渡放大细胞的增殖反应的损害。最后，将使用TNFa受体基因敲除小鼠来剖析炎症对矽肺细支气管壁上皮再生能力受损的作用(Aim 3)。这些研究的最终目标是确定矽肺如何损害干细胞层级，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。这项建议研究了二氧化硅粉尘如何削弱肺内干细胞修复肺损伤而不形成疤痕的能力。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。在申请表的第二页中，在表格底部连续编号。不要使用2a、2b等后缀。