Angiopoietins in vascular and lymphatic remodeling of airways and lung

描述（由申请方提供）：本项目将检验血管生成素通过调节血管和血管重塑影响气道和肺部炎症反应的严重程度和持续时间的总体假设。这种性质使血管生成素成为重要的治疗靶点。目的是在临床前实验中确定血管生成素的作用，通过使用目前正在开发的血管生成素激动剂和抑制剂，可用于治疗人类炎症性肺病。血管生成素控制血管和血管生成物的生长和稳定性：血管生成素-1（Ang 1）激活内皮细胞上的Tie 2受体，血管生成素-2（Ang 2）抑制或激活Tie 2信号传导，这取决于环境和时空浓度。该项目将探索血管生成素对两个相互关联的过程具有有效作用的证据：（1）血管重塑，影响血浆渗漏和白细胞流入的量，以及（2）淋巴重塑，影响水肿液清除和免疫细胞向淋巴结的运输。该方法将使用三种肺部炎症的小鼠模型，由于支原体感染，真菌过敏原挑战或肺纤维化，与功能试剂和转基因小鼠的互补增益或损失，作为工具来询问血管生成素在临床相关炎症条件下的作用。具体目标#1将评估在炎症中血管重塑的两个阶段中操纵血管生成素作用的益处。在I期，Ang 2对Tie 2信号传导的抑制促进周细胞-内皮细胞附着的松动、血管不稳定、渗漏和白细胞粘附蛋白的表达。在第二阶段，周细胞增殖并加强异常血管表型，维持渗漏和白细胞运输。目的#1将检验以下假设：Ang 2抑制或Ang 1激活Tie 2可通过逆转导致并维持渗漏和白细胞流入的血管重塑来减轻肺部炎症。具体目标#2将探索在炎症部位纠正淋巴缺陷的策略，在炎症部位，淋巴管重塑损害液体清除和免疫细胞运输。目的#2将检验以下假设：Ang 1抑制Ang 2或激活Tie 2促进淋巴成熟和形成有效引流液体所需的特化纽扣样内皮连接。目的#2还将通过研究呼吸道上皮中条件性VEGF-C过表达的新型转基因小鼠，研究在肺淋巴管扩张和乳糜胸中操纵血管生成素作用的益处，其中扩张的充满液体的通道取代正常的肺毛细血管。总之，这些实验将探索操纵血管生成素作用的治疗潜力，通过调节血管和动脉的重塑来减少气道和肺部的水肿和炎症。

DESCRIPTION (provided by applicant): This project will test the overall hypothesis that angiopoietins influence the severity and duration of inflammatory responses in the airways and lung, by regulating the remodeling of blood vessels and lymphatics. This property makes angiopoietins important therapeutic targets. The goal is to determine in preclinical experiments the actions of angiopoietins that can be exploited in the treatment of human inflammatory lung disease, through the use of angiopoietin agonists and inhibitors currently under development. Angiopoietins control the growth and stability of blood vessels and lymphatics: angiopoietin-1 (Ang1) activates Tie2 receptors on endothelial cells, and angiopoietin-2 (Ang2) inhibits or activates Tie2 signaling, depending on context and temporal-spatial concentrations. The project will explore evidence that angiopoietins have potent actions on two interrelated processes: (1) blood vessel remodeling, which influences the amount of plasma leakage and leukocyte influx, and (2) lymphatic remodeling, which influences edema fluid clearance and immune cell traffic to lymph nodes. The approach will use three mouse models of lung inflammation, due to mycoplasmal infection, fungal allergen challenge, or pulmonary fibrosis, with complementary gain or loss of function reagents and transgenic mice, as tools to interrogate the actions of angiopoietins in clinically relevant inflammatory conditions. Specific Aim #1 will assess the benefit of manipulating angiopoietin actions in two phases of blood vessel remodeling in inflammation. In Phase I, suppression of Tie2 signaling by Ang2 promotes loosening of pericyte-endothelial cell attachment, vessel destabilization, leakiness, and expression of leukocyte-adhesion proteins. In Phase II, pericytes proliferate and reinforce the abnormal vascular phenotype that sustains leakage and leukocyte traffic. Aim #1 will test the hypothesis that Ang2 inhibition or Tie2 activation by Ang1 can reduce lung inflammation by reversing vascular remodeling that leads to and sustains leakage and leukocyte influx. Specific Aim #2 will explore strategies for correcting lymphatic defects at sites of inflammation, where remodeling of lymphatics impairs fluid clearance and immune cell traffic. Aim #2 will test the hypothesis that Ang2 inhibition or Tie2 activation by Ang1 promotes lymphatic maturation and formation of specialized button-like endothelial junctions necessary for efficient fluid drainage. Aim #2 will also investigate the benefit of manipulating angiopoietin actions in pulmonary lymphangiectasia and chylothorax, where dilated fluid-filled channels replace normal lung lymphatics, by studying a novel transgenic mouse with conditional VEGF-C overexpression in the respiratory epithelium. Together, the experiments will explore the therapeutic potential of manipulating angiopoietin actions to reduce edema and inflammation in the airways and lung by regulating the remodeling of blood vessels and lymphatics.