Role of p120-catenin in sepsis-induced lung injury

p120-catenin在脓毒症肺损伤中的作用 该项目的首要主题是描述p120的新型免疫调节功能- 连环蛋白（p120）在缓解肺损伤和炎症中的作用。支持这一更新的关键观察结果 一项提案（在支持性数据中提出）表明，p120表达的重要宿主防御功能， 巨噬细胞在调节凋亡中性粒细胞的清除（巨噬细胞增多症）中的作用。我们观察到p120的缺失 在巨噬细胞中的表达严重损害了巨噬细胞吞噬凋亡细胞的能力。 中性粒细胞巨噬细胞中特异性p120消融显著延迟炎症性肺损伤的恢复， 败血症的鼠模型。这些结果提出了几个对肺的宿主防御至关重要的基本问题 功能，将在本提案中解决，包括：p120如何调节吞噬作用 凋亡中性粒细胞？这是p120介导的功能需要解决炎症性肺损伤？可以 表达p120基因工程巨噬细胞肺移植促进肺修复 受伤？虽然p120是上皮和内皮细胞中粘附连接的一种良好描述的成分， 我们在上一轮拨款中的研究表明，内皮细胞p120可以保护肺部， 通过抑制Toll样受体4信号传导来减轻脓毒症诱导的损伤。在这次更新建议中，我们将重点关注 定义以前未被认识的p120在肺巨噬细胞中的功能， 炎症和肺修复的解决，如果是这样的话，介导p120这种作用的潜在机制。 因此，我们将检验肺巨噬细胞中的p120有助于缓解 炎症性肺损伤的机制。这一假设将由以下人员进行检验： 针对以下具体目标。在目标1中，我们将定义p120 调节肺巨噬细胞吞噬凋亡中性粒细胞的能力。在目标2中，我们 探讨肺巨噬细胞p120作为一种重要蛋白在肺巨噬细胞凋亡中的作用 炎症性肺损伤的机制。我们希望通过这些研究提供重要和有用的 深入了解p120在肺损伤发病机制和修复过程中的作用。完成后 通过这些研究，我们将对肺巨噬细胞p120作为一种免疫调节因子的作用有更清楚的认识。 肺免疫功能的潜在重要的和新的调节剂，并且还作为潜在的治疗靶点， 促进炎性肺损伤的消退。

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.