Pathophysiology of Alveolar Epithelial Lung Injury

该计划项目资助申请是基于这样的假设，即在肺损伤期间，肺泡上皮细胞功能的恢复对于预防无序愈合、纤维化以及急性呼吸窘迫综合征（ARDS）患者的结局至关重要。我们已经组建了一个高度互动的调查小组，他们在上一个赠款周期中合作，富有成效和协同作用。我们建议通过三个相互关联的项目和三个支持核心来研究肺泡上皮细胞的损伤和修复。在项目1中，我们将重点关注缺氧时调节肺泡上皮功能的机制，因为它涉及Na，K-ATP酶磷酸化-内吞作用和泛素化-降解。在项目2中，我们将确定中间丝在肺泡上皮损伤修复和重塑中的作用。在项目3中，我们将研究肺泡上皮细胞凋亡在肺损伤和修复过程中的作用机制。对每个项目都进行了合作研究，初步结果支持这一建议的可行性。该计划项目的重点是研究人员的多学科专业知识，阐明在临床相关的损伤模型中导致肺上皮细胞损伤的机制。这些项目在概念上和程序上都是互动的，其中项目的总和大于其部分的总和。他们的集体结果将提供一个复合图片的Na，K-ATP酶和中间丝在肺泡上皮细胞损伤过程中的调节，并确定肺泡上皮细胞凋亡在肺损伤的发病机制中的作用。从这些研究产生的数据中获得的见解将为开发治疗肺损伤患者的新治疗策略提供新的分子靶点。

This Program Project Grant application is founded on the hypothesis that during lung injury, recovery of alveolar epithelial cell function is of crucial importance in the prevention of disordered healing, fibrosis and thus the outcome of patients with the acute respiratory distress syndrome (ARDS). We have assembled a highly interactive group of investigators who have worked collaboratively, productively and synergistically in the previous cycle of the grant. We propose to study alveolar epithelial cell injury and repair via three interrelated projects and three supportive cores. In Project # 1 we will focus on the mechanisms regulating alveolar epithelial function during hypoxia as it pertains to Na,K-ATPase phosphorylation-endocytosis and ubiquitination-degradation. In Project # 2 we will determine the role of intermediate filaments in alveolar epithelial wound repair and remodeling. In Project # 3 we will investigate the mechanisms of alveolar epithelial apoptosis in the development of lung injury and repair. Collaborative studies have been conducted for each of the projects and the preliminary results support the feasibility of this proposal. This Program Project focuses the multidisciplinary expertise of the investigators on the elucidation of mechanisms contributing to lung epithelial cell injury in clinically relevant models of injury. These projects are interactive conceptually and programmatically, where the aggregate of the projects is greater than the sum of its parts. Their collective outcome will provide a composite picture of the regulation of the Na,K-ATPase and intermediate filaments in the alveolar epithelium during injury and determine the role of alveolar epithelial cell apoptosis in the pathogenesis of lung injury. The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury.