Derangements of the Notch Pathway in Airway Epithelial Differentiation in COPD

在正常人的呼吸道中，作为对损伤的反应，有上皮细胞再生 基底细胞增殖和随后分化维持正常假复层 上皮组织。但作为慢性阻塞性肺疾病(COPD)的临床表型 随着疾病的进展，呼吸道上皮的分化状态开始改变，如 上皮层厚度增加，基底细胞比例增加，纤毛细胞减少， 杯状细胞增生，最终鳞状化生。除了由以下因素引起的伤害 吸烟和炎症，有越来越多的证据表明COPD的发展是 与腺病毒潜伏的上皮感染有关。这个项目的重点是 呼吸道上皮细胞基因表达变化与其分化状态改变的关系 慢性阻塞性肺疾病（慢阻肺）。基因表达微阵列与发育相关基因芯片的初步研究 生物学文献表明Notch信号通路在呼吸道上皮细胞中起关键作用 差异化。Notch被认为是对抗差异化的主要“看门人”，激活 Notch通路阻断分化，而该通路的抑制与 允许细胞朝着特定的命运前进。基于这一背景， 该项目旨在检验慢性阻塞性肺疾病与以下疾病的错乱有关的假设 Notch信号通路在气道上皮细胞中的表达，参与了慢性阻塞性肺疾病的异常模式 呼吸道上皮细胞分化是这种疾病的特征。为了检验这一假设， 提出了以下具体目标。具体目标1.评估凹槽的假设 COPD患者的呼吸道上皮细胞中信号通路被激活。具体目标2.至 检验一种假设，即在正常情况下，呼吸道上皮损伤后不能再生 慢性阻塞性肺疾病的流行，部分原因是Notch信号的正常通路紊乱。 具体目的3.检验C组腺病毒感染在精神障碍中起作用的假设 慢性阻塞性肺疾病患者呼吸道上皮细胞中的缺口信号。

In the airway of normal individuals and in response to injury, there is epithelial cell regeneration with basal cell proliferation and subsequent differentiation to maintain the normal pseudostratified epithelium. But as the clinical phenotype of chronic obstructive pulmonary disease (COPD) progresses, the differentiation status of the airway epithelium begins to change as indicated by an increased thickness of the epithelial layer, with proportionally more basal cells and less ciliated cells, goblet cell hyperplasia, and eventually squamous metaplasia. In addition to the injury mediated by cigarette smoke and inflammation, there is increasing evidence that the development of COPD is associated with latent infection of the epithelium with adenoviruses. The focus of this project is on the changes of gene expression in the airway epithelium that contribute to its altered differentiated state in COPD. Our preliminary studies with gene expression microarrays combined with the developmental biology literature have implicated the Notch signaling pathway as being critical to airway epithelial differentiation. Notch is considered a primary "gatekeeper" against differentiation, with activation of the Notch pathway blocking differentiation, whereas suppression of the pathway is associated with allowing the cells to proceed toward a specific fate. Based on this background, the studies proposed in this project are designed to test the hypothesis that COPD is associated with derangements of the Notch signaling pathway in the airway epithelium, contributing to the abnormal pattern of airway epithelial differentiation that characterizes this disorder. To test this hypothesis the following specific aims are proposed. Specific aim 1. To evaluate the hypothesis that the Notch signaling pathway is activated in the airway epithelium of individuals with COPD. Specific aim 2. To examine the hypothesis that the airway epithelium cannot regenerate following injury in a normal fashion in COPD, in part, because the normal pathways of the Notch signaling are disordered. Specific aim 3. To test the hypothesis that group C adenovirus infection plays a role in the disordered Notch signaling in the airway epithelium in COPD.