Role of p120-catenin in sepsis-induced lung injury

P120-连环蛋白在脓毒症肺损伤中的作用 这个项目的主要主题是描绘p120的新的免疫调节功能- 连环蛋白(P120)在解决肺损伤和炎症中的作用。支撑这一更新的关键观察 建议(在支持数据中提出)表明p120表达的基本宿主防御功能 巨噬细胞在调节中性粒细胞凋亡清除中的作用(胞吐)。我们观察到p120的丢失 巨噬细胞表达严重损害巨噬细胞吞噬细胞凋亡的能力 中性粒细胞。巨噬细胞特异性p120消融明显延缓炎性肺损伤的恢复 脓毒症小鼠模型。这些结果提出了几个对肺脏的宿主防御至关重要的基本问题 这项建议将涉及的功能，包括：p120如何调节吞噬 凋亡的中性粒细胞？这种p120介导的功能是解决炎症性肺损伤所必需的吗？能 表达p120基因工程巨噬细胞肺移植促进肺修复 受伤了吗？虽然p120是上皮细胞和内皮细胞中黏附连接的一种很好的描述成分， 我们在上一轮拨款中的研究表明，内皮细胞p120保护肺。 通过抑制Toll样受体4信号通路，减轻脓毒症引起的损伤。在这份续签提案中，我们将重点关注 确定肺巨噬细胞中p120以前未知的功能以及它是否协调 炎症的消解和肺的修复，如果是这样的话，调节p120这一作用的潜在机制。 因此，我们将检验这一中心假设，即肺巨噬细胞中的p120有助于解决 调节胞吐相关信号的炎症性肺损伤。这一假设将通过以下方式检验 解决以下具体目标。在目标1中，我们将定义p120的分子机制 调节肺巨噬细胞吞噬凋亡的中性粒细胞的能力。在目标2中，我们将 评价肺巨噬细胞p120作为一种必需蛋白在分解过程中的功能意义 炎症性肺损伤的机制。我们希望通过这些研究为我们提供重要和有用的 深入了解p120在肺损伤的发病机制和修复过程中的作用。随着工程的完成 通过这些研究，我们将更清楚地了解肺巨噬细胞p120作为一种 潜在的重要和新的肺免疫功能调节剂，也是潜在的治疗靶点 促进炎症性肺损伤的消退。

Role of p120-catenin in sepsis-induced lung injury The overarching theme of this project is the delineation of the novel immunomodulatory function of p120- catenin (p120) in resolving lung injury and inflammation. The crucial observations underpinning this renewal proposal (presented in Supporting Data) suggest an essential host-defense function of p120 expression in macrophages in regulating clearance of apoptotic neutrophils (efferocytosis). We observed that loss of p120 expression in macrophages severely impaired the ability of macrophages to phagocytose the apoptotic neutrophils. Specific p120 ablation in macrophages markedly delayed recovery of inflammatory lung injury in a murine model of sepsis. These results raise several fundamental questions central to lung’s host-defense function that will be addressed in this proposal, including: How does p120 regulate the phagocytosis of apoptotic neutrophils? Is this p120-mediated function required for resolving inflammatory lung injury? Can pulmonary transplantation of genetically engineered macrophage expressing p120 accelerate repair of lung injury? Although p120 is a well-described constituent of adherens junctions in epithelial and endothelial cells, our studies during the previous cycle of the grant have demonstrated that endothelial p120 protected the lungs from sepsis-induced injury by inhibiting Toll-like receptor 4 signaling. In this renewal proposal, we will focus on defining previously unrecognized function of p120 in pulmonary macrophages and whether it orchestrates resolution of inflammation and lung repair and, if so, the underlying mechanisms mediating this action of p120. Thus we will test the central hypothesis that p120 in pulmonary macrophages favors resolution of inflammatory lung injury by modulating efferocytosis-related signaling. This hypothesis will be tested by addressing the following Specific Aims. In Aim 1, we will define the molecular mechanisms by which p120 regulates the ability of pulmonary macrophages to phagocytize apoptotic neutrophils. In Aim 2, we will evaluate the functional significance of pulmonary macrophage p120 as an essential protein in the resolution mechanism of inflammatory lung injury. We hope through these studies to provide important and useful insights into the role of p120 in the pathogenesis of lung injury and in the repair processes. With the completion of these studies, we will have a more clear understanding of the role of pulmonary macrophage p120 as a potentially important and novel modulator of lung immune function and also as a potential therapeutic target to promote resolution of inflammatory lung injury.