Angiopoietins in vascular and lymphatic remodeling of airways and lung

描述(由申请者提供)：该项目将测试血管生成素通过调节血管和淋巴管的重塑来影响呼吸道和肺部炎症反应的严重程度和持续时间的总体假设。这一特性使血管生成素成为重要的治疗靶点。其目标是在临床前实验中确定可通过使用目前正在开发的血管生成素激动剂和抑制剂来治疗人类炎症性肺病的血管生成素的作用。血管生成素控制血管和淋巴管的生长和稳定：血管生成素-1(Ang1)激活内皮细胞上的Tie2受体，血管生成素-2(Ang2)抑制或激活Tie2信号，这取决于背景和时空浓度。该项目将探索血管生成素在两个相互关联的过程中具有强大作用的证据：(1)血管重塑，影响血浆渗漏和白细胞内流的数量；(2)淋巴重塑，影响水肿液的清除和免疫细胞向淋巴结的运输。该方法将使用支原体感染、真菌过敏原攻击或肺纤维化引起的三种小鼠肺部炎症模型，以及互补的功能获得或丧失试剂和转基因小鼠，作为询问血管生成素在临床相关炎症条件下的作用的工具。具体目标#1将评估在炎症血管重塑的两个阶段操纵血管生成素作用的益处。在第一阶段，Ang2抑制Tie2信号促进周细胞-内皮细胞附着松动、血管不稳定、渗漏和白细胞黏附蛋白的表达。在第二阶段，周细胞增殖并加强异常的血管表型，从而维持渗漏和白细胞运输。目的1验证Ang2抑制或激活Tie2可通过逆转导致和维持渗漏和白细胞内流的血管重塑来减轻肺部炎症的假说。具体目标#2将探索纠正炎症部位淋巴缺陷的策略，在炎症部位，淋巴管重塑损害液体清除和免疫细胞交通。目的#2将验证这样一个假设，即Ang2抑制或激活Tie2可促进淋巴管成熟和形成有效液体排出所必需的特殊纽扣状内皮连接。目的#2还将通过研究一种新的呼吸道上皮条件表达血管内皮生长因子-C的转基因小鼠，研究血管生成素在肺淋巴管扩张症和乳糜胸中的作用，在这些疾病中，扩张的充液通道取代了正常的肺淋巴管。总之，这些实验将探索通过调节血管和淋巴管的重塑来操纵血管生成素的作用，以减少呼吸道和肺部的浮肿和炎症的治疗潜力。

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.