Lung Endothelial Cell Phenotypes

描述(申请人提供)：内皮连接血管，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的内皮细胞之间，在器官内单个血管段的内皮细胞中，甚至在紧邻的细胞之间都是明显的。在肺循环中，肺泡外血管内皮细胞与毛细血管段内皮细胞明显不同。该计划项目拨款建立在这样的总体假设基础上，即肺动脉、毛细血管和静脉内皮细胞表型不同；每种细胞类型都高度专业化，以满足其血管利基的独特需求。我们对这种异质性是如何实现以控制特定部位的血管需求，特别是在肺的微血管间隔中的了解有限。因此，修改后的更新应用的一个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，在最终导致急性肺损伤的感染过程中，肺部微血管内皮细胞功能会受到细菌的损害，如铜绿假单胞菌。因此，肺微血管内皮细胞是对抗急性肺损伤血管功能障碍的潜在治疗靶点。项目在概念上和实践上都具有高度的互动性。该计划项目赠款利用不同研究领域的新发展，并应用这些发展来产生关于微血管内皮细胞如何对炎症做出反应以及它们如何在损伤后修复的新信息。明确肺微血管内皮细胞功能的机制将使我们深入了解肺血管疾病的部位特异性，并使我们最终能够开发合理的药物治疗来离散干预所有已知的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.