Lung Endothelial Cell Phenotypes

描述（由申请人提供）： 虽然内皮在历史上被认为是一个均匀的细胞层，但越来越多的人认识到它在结构和功能上表现出丰富的多样性。异质性在不同器官的内皮细胞之间、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。该计划项目资助是建立在这样的假设之上的，即肺的肺泡外和肺泡血管的内皮细胞在表型上是不同的，并且来自这些不同血管位置的细胞的独特行为是它们实现其位点特异性功能所必需的。我们目前对这种异质性如何实现以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中。因此，这种竞争性更新应用的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这种细胞类型的行为信息相对缺乏。我们提出了四个相互关联的项目，检查不同的信号转导级联控制肺微血管内皮细胞的行为，包括渗透性调节（史蒂文斯，项目1和汤斯利，项目4），凋亡/坏死（吉莱斯皮，项目2），和血管性血友病因子分泌（吴，项目3）。这些项目在概念上和实际上都具有高度的互动性。为此，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生成有关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): 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.