Molecular & functional aspects of vascular permeability

血管内皮的主要功能是调解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，这个功能显然是“至关重要的”。虽然已经确定了涉及跨内皮交换的形态学结构（即小泡、跨内皮通道、窗和细胞间连接），但关于相关结构的分子组成、其生物发生和调控的生化证据很少甚至没有。本研究的主要目的是阐明内皮分化的具体化学成分和功能，如窗和小泡及其气孔隔膜。该发现还将记录跨内皮转运的一个新方面，即其调节的可能性和方式（运输的速率和成分）。除了对跨内皮转运的正常生理过程的理解产生影响外，这些数据还可以进一步用于研究几种人类疾病（如肿瘤血管生成、糖尿病、视网膜病变、牛皮癣、肺病、纤维化、血小板减少症、过敏性脑脊髓炎、动脉高血压）的病理生理学，这些疾病已显示出这种转运调节的发生。这些研究还可以提供新的运输相关内皮特异性分子标记，可用于设计药物和基因靶向微血管床的策略。所采用的技术有细胞分离、细胞自由测定、体内筛选方法、二维电泳、细胞培养、转染、光镜和电镜。

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.