Molecular & functional aspects of vascular permeability

血管内皮细胞的主要功能是调节和控制血浆和间质液之间的水和溶质(包括小分子和大分子)的跨内皮交换。从所有组织和器官的所有细胞对它的依赖程度来看，这一功能显然是“至关重要的”。虽然涉及跨内皮细胞交换的形态结构(即小窝、跨内皮通道、窗孔和细胞间连接)已被鉴定，但有关这些结构的分子组成、生物发生和调控的生化证据很少或根本没有。这项研究的主要目标是阐明内皮分化的特定化学成分和功能，如窗孔和小凹及其气孔隔膜。这一发现还将证明跨内皮细胞运输的一个新方面，即其调节的可能性和方式(在速率和运输成分方面)。这些数据除了对了解血管内皮细胞转运的正常生理过程有影响外，还可以用来进一步研究几种人类疾病(如肿瘤血管生成、糖尿病、视网膜病变、银屑病、肺、纤维化、血小板减少症、过敏性脑脊髓炎、动脉高压)的病理生理学。这些研究还可以提供新的运输相关的内皮特异性分子标记，可用于设计针对选定微血管床的药物和基因靶向策略。所使用的技术包括细胞分离、细胞游离分析、体内筛选方法、双向电泳法、细胞培养、转染法、光学显微镜和电子显微镜。

The main function of vascular endothelium is the mediation and control of transendothelial exchanges of water and solutes (both small and large molecules) between blood plasma and the interstitial fluid. This function IS OBVIOUSLY "vital", judged on the dependency on it of all the cells from all tissues and organs. While the morphological structures involved in transendothelial exchanges have been identified (i.e. caveolae, transendothelial channels, fenestrae and intercellular junctions), there is very little to no biochemical evidence on the molecular composition of the structures involved, their biogenesis and regulation. The major goals of this research proposal are to elucidate the specific chemical composition and function of the endothelial differentiations such as fenestrae and caveolae and their stomatal diaphragms. The finding will also document a novel aspect of the transendothelial transport namely the possibility and ways of its modulation (in rate and components transported). Besides their impact on the understanding of the normal physiological process of the transendothelial transport, the data could be used further in the study of the pathophysiology of several human diseases (e.g. tumor angiogenesis, diabetes, retinopathy, psoriasis, pulmonary, fibrosis, thrombocytopenia, allergic encephalomyelitis, arterial hypertension) where such transport modulations have been shown to occur. These studies could also provide novel transport related endothelial specific molecular markers that could be used in designing strategies for drugs and gene targeting to selected microvascular beds. The techniques employed are cell fractionation, cell free-assays, in-vivo screening methods, two- dimensional electrophoresis, cell culture, transfections, light and electron microscopy.