Lung Endothelial Cell Phenotypes

描述(由申请人提供)： 虽然内皮细胞历来被认为是一种同质细胞层，但越来越多的人意识到它在结构和功能上表现出丰富的多样性。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，以及实际上，在紧邻的细胞之间，异质性是明显的。本项目基于这样一个假设：肺泡外血管和肺泡血管内皮细胞的表型是不同的，来自这些不同血管位置的细胞的独特行为是它们履行其特定部位功能所必需的(S)(S)。我们目前对这种异质性是如何实现来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，这种竞争性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其毛细血管功能的分子机制。我们对微血管内皮细胞表型的关注是基于关于这类细胞行为的信息相对匮乏。我们提出了四个相互关联的项目，研究控制肺微血管内皮细胞行为的不同信号转导级联，包括通透性调节(Stevens，项目1和Townsley，项目4)，凋亡/坏死(Gillesbie，项目2)，以及von Willebrand因子分泌(Wu，项目3)。这些项目在概念和实践上都具有很强的互动性。为此，本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肺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): While endothelium has historically been considered a homogeneous cell layer, there is an increasing appreciation that it exhibits a rich diversity in structure and function. 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. This Program Project Grant is founded on the hypothesis that endothelium lining the lung's extra-alveolar and alveolar blood vessels is phenotypically distinct, and that the unique behavior(s) of cells from these different vascular locations is necessary for them to fulfill their sitespecific function(s). We currently 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 competitive renewal application is therefore to rigorously determine molecular mechanisms that allow lung microvascular endothelial cells to successfully control their capillary function. Our focus on the microvascular endothelial cell phenotype is based upon the relative paucity of information regarding the behavior of this cell type. We propose four inter-related projects examining different signal transduction cascades that control lung microvascular endothelial cell behavior, including permeability regulation (Stevens, Project 1 and Townsley, Project 4), apoptosis/necrosis (Gillespie, Project 2), and von Willebrand factor secretion (Wu, Project 3). These projects are highly interactive both conceptually and pragmatically. Toward this end, this Program Project Grant draws on emerging developments in different fields of study, and applies these developments to generate new information about how microvascular lung 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 the endothelial cell dysfunction that occurs in all known pulmonary vascular diseases.