Structure and Function of Endothelial Fenestrae

血管内皮的主要功能是介导和控制跨内皮细胞的 水和溶质（小分子和大分子）在血浆和血管之间的交换 间质液，简而言之，控制血管通透性。这一功能显然是“至关重要的”， 对于所有组织和器官的所有细胞的正常生长、维持和存活至关重要。也是 是炎症防御机制的重要组成部分。而 已经鉴定了涉及跨内皮交换的形态结构（即小窝， 内皮特异性细胞器，例如跨内皮通道、窗孔、囊泡-空泡 细胞器以及细胞间连接），除了小窝和细胞间连接外， 连接处，很少或没有关于结构分子组成的生化证据 参与，它们的生物起源和调节。这项研究的主要目的是阐明 内皮窗生物发生的机制。除了它们对正常人的理解的影响外， 生理过程的跨内皮交换，数据可用于进一步研究， 几种人类疾病的病理生理学，如肿瘤血管生成、急性和慢性 炎症（病毒和细菌感染，移植排斥，过敏性脑脊髓炎， 阿尔茨海默病）、动脉粥样硬化、先兆子痫、中毒性肝损伤和肝硬化，其中调节 内皮窗已经显示出发生。这些研究也可以帮助设计新的策略， 药物和基因靶向选定的微血管床。所采用的技术是细胞分离， 分级分离，生物化学测定，无细胞测定，遗传修饰的动物模型，细胞培养， 转染，光学和电子显微镜。

The main function of the vascular endothelium is the mediation and control of the transendothelial exchanges of water and solutes (both small and large molecules) between blood plasma and the interstitial fluid, in short the control of vascular permeability. This function is obviously “vital”, being critical for normal growth, maintenance and survival of all the cells from all tissues and organs. It is also an important contributor to the defense mechanisms that occur in inflammation. While the morphological structures involved in transendothelial exchanges have been identified (i.e. caveolae, endothelial specific organelles such as transendothelial channels, fenestrae, vesiculo-vacuolar organelles as well as intercellular junctions), with the exception of caveolae and the 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 mechanism of endothelial fenestrae biogenesis. Besides their impact on the understanding of the normal physiological process of the transendothelial exchange, the data could be used further in the study of the pathophysiology of several human diseases such as tumor angiogenesis, acute and chronic inflammation (both viral and bacterial infections, transplant rejection, allergic encephalomyelytis, Alzheimer disease), atherosclerosis, preeclampsia, toxic liver injury and cirrhosis where modulations of endothelial fenestrae have been shown to occur. These studies could also help in designing novel strategies for drugs and gene targeting to selected microvascular beds. The techniques employed are cell isolation, fractionation, biochemical assays, cell free-assays, genetically modified animal models, cell culture, transfections, light and electron microscopy.