Lung Endothelial Cell Phenotypes

描述（由申请人提供）：内皮素内衬血管，并连接所有器官系统。人们越来越认识到内皮细胞在结构和功能上表现出丰富的多样性。这种异质性在不同器官中的内皮细胞之间、在器官内沿沿着单个血管段的内皮细胞中以及实际上在紧邻的细胞之间是明显的。在肺循环中，肺泡外血管的内皮细胞与毛细血管段的内皮细胞明显不同。该计划项目资助是建立在肺动脉，毛细血管和静脉内皮细胞的表型不同的整体假设上;每种细胞类型都是高度专业化的，以满足其血管生态位的独特需求。我们对这种异质性是如何达到控制部位特异性血管需求的理解有限，特别是在肺的微血管区室。因此，本修订更新申请的主要目标是严格确定允许肺微血管内皮细胞成功控制毛细血管功能的分子机制。此外，肺微血管内皮细胞功能在急性肺损伤中达到高潮的感染期间被细菌如铜绿假单胞菌损害。因此，肺微血管内皮代表了对抗急性肺损伤中血管功能障碍的假定治疗靶点。本次修订更新中的三个项目系统地研究了调节内皮细胞渗透性和中性粒细胞迁移的机制;每个项目都有三个具体目标，即：（1）识别和测试新的分子机制（例如信号），其控制位点特异性内皮细胞功能，特别是集中于微循环，（2）确定这些机制在疾病的临床前模型中的重要性，以及（3）在疾病的临床前模型中转化新的治疗方法。项目在概念上和实际上都是高度互动的。该计划项目资助借鉴了不同研究领域的新兴发展，并将这些发展应用于产生有关微血管内皮细胞如何对炎症反应以及损伤后如何修复的新信息。明确肺微血管内皮细胞功能的机制将有助于深入了解肺血管疾病的部位特异性，并使我们能够最终开发出合理的药物治疗方法，以离散地干预所有已知肺血管疾病中发生的内皮细胞功能障碍。

DESCRIPTION (provided by applicant): Endothelium lines blood vessels, and inter-connects all organ systems. There has been a growing appreciation that endothelial cells exhibit a rich diversity in structure and function. Such heterogeneity is apparent between endothelial cells in different organs, in endothelial cells along a single vascular segment within an organ and, indeed, between immediately adjacent cells. In the pulmonary circulation, endothelium in extra-alveolar blood vessels differs markedly from those in capillary segments. This program project grant is founded on the overall hypothesis that endothelium lining pulmonary arteries, capillaries, and veins is phenotypically distinct; each cell type is highly specialized to fulfill he unique demands of its vascular niche. We possess a limited understanding of how such heterogeneity is achieved to control site specific vascular demands, particularly in the lung's microvascular compartment. A principal goal in this amended renewal application is therefore to rigorously determine molecular mechanisms that allow lung microvascular endothelial cells to successfully control capillary function. Moreover, lung microvascular endothelial cell function is impaired by bacteria, such as Pseudomonas aeruginosa, during infection that culminates in acute lung injury. Hence, pulmonary microvascular endothelium represents a putative therapeutic target to combat vascular dysfunction in acute lung injury. The three projects in this amended renewal systematically study mechanisms regulating endothelial cell permeability and neutrophil transmigration; each project addresses three specific objectives, to: (1) identify and test novel molecular mechanisms (e.g. signatures) that control site-specific endothelial cell function, especially focusing on the microcirculation, (2) determine the importance of these mechanisms in preclinical models of disease, and (3) translate novel therapeutic approaches in preclinical models of disease. Projects are highly interactive both conceptually and pragmatically. This Program Project Grant draws on emerging developments in different fields of study, and applies these developments to generate new information about how microvascular endothelial cells, in particular, respond to inflammation and how they repair following injury. Defining the mechanisms that underlie lung microvascular endothelial cell function will provide insight into the site-specific nature of pulmonary vascular disease, and allow us to ultimately develop rational pharmacological therapies to discretely intervene in endothelial cell dysfunction that occurs in all known pulmonary vascular diseases.