Lung Endothelial Cell Phenotypes

描述（申请人提供）：内皮细胞连接血管，连接所有器官系统。内皮细胞在结构和功能上表现出丰富的多样性，这一点越来越受到人们的重视。这种异质性在不同器官的内皮细胞之间，在一个器官内单个血管段的内皮细胞之间，以及在紧邻的细胞之间都是明显的。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。这个项目的资助是基于肺动脉、毛细血管和静脉的内皮细胞在表型上是不同的这一假设；每种细胞类型都是高度特化的，以满足其血管生态位的独特需求。我们对如何实现这种异质性来控制特定部位的血管需求，特别是在肺微血管室，了解有限。因此，这个修订后的更新应用程序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，在感染期间，肺微血管内皮细胞功能受到细菌的损害，如铜绿假单胞菌，最终导致急性肺损伤。因此，肺微血管内皮被认为是对抗急性肺损伤血管功能障碍的治疗靶点。这三个项目在这个修订的更新系统地研究调节内皮细胞通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：(1)识别和测试控制特定部位内皮细胞功能的新分子机制（例如特征），特别是关注微循环；(2)确定这些机制在疾病临床前模型中的重要性；(3)将新的治疗方法转化为疾病临床前模型。项目在概念上和实际操作上都是高度互动的。本项目利用不同研究领域的新兴发展，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损伤后如何修复的新信息。确定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，并使我们最终能够开发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.