Pathophysiology of Alveolar Epithelial Lung Injury

本项目资助申请基于以下假设：在肺损伤过程中，肺泡上皮细胞功能的恢复对于预防愈合紊乱、纤维化以及急性呼吸窘迫综合征（ARDS）患者的预后至关重要。我们已经组建了一个高度互动的研究小组，他们在前一个资助周期中进行了协作，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肺泡上皮功能的调节机制，因为它与Na， k - atp酶磷酸化-内吞作用和泛素化-降解有关。在项目# 2中，我们将确定中间纤维在肺泡上皮伤口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发生和修复中的机制。每个项目都进行了合作研究，初步结果支持这项建议的可行性。本项目集中研究人员的多学科专业知识，阐明在临床相关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编程上是交互的，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损伤期间肺泡上皮内Na、k - atp酶和中间丝调节的综合图景，并确定肺泡上皮细胞凋亡在肺损伤发病机制中的作用。从这些研究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.