Structure and Function of Endothelial Fenestrae

内皮窗孔的结构和功能

• 批准号: 7730256
• 负责人: RADU VIRGIL STAN
• 金额: $ 46.25万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7730256
• 关键词: Actins; Acute; Adult; Allergic; Alzheimer' s Disease; Animal Model; Atherosclerosis; Automobile Driving; Bacterial Infections; Biochemical; Biogenesis; Biological Assay; Blood; Blood Vessels; Breeding; CAV1 gene; Cardiovascular system; Caveolae; Cell Culture Techniques; Cell Separation; Cell membrane; Cells; Chronic; Cirrhosis; Cytoskeleton; Data; Databases; Defense Mechanisms; Disease; Electron Microscopy; Electrons; Embryo; Endocytosis; Endocytosis Pathway; Endothelial Cells; Endothelium; Event; Excision; Exocytosis; Fluorescent Probes; Fractionation; Functional disorder; Funding; Gene Targeting; Genetic; Genetically Modified Animals; Goals; Graft Rejection; Growth; Heart; Image; Immunoblotting; Immunofluorescence Immunologic; In Situ; Inflammation; Injury; Intercellular Fluid; Intercellular Junctions; Kidney; Kidney Glomerulus; Knowledge; Life; Light; Liquid substance; Literature; Liver; Maintenance; Mediation; Microcirculatory Bed; Microscopy; Molecular; Molecular Structure; Morphology; Mus; Nutrient; Organ; Organelles; Oxygen; Pancreas; Permeability; Pharmaceutical Preparations; Phenotype; Physiological Processes; Plasma; Play; Pre-Eclampsia; Process; Proteins; Regulation; Research; Research Proposals; Respiratory Diaphragm; Role; Scanning Transmission Electron Microscopy Procedures; Small Interfering RNA; Staging; Structure; Subcellular structure; System; Techniques; Testing; Tissues; Transfection; Transgenic Organisms; Treatment Efficacy; Tumor Angiogenesis; Vascular Endothelium; Vascular Permeabilities; Viral; Water; Work; base; data exchange; design; human disease; inhibitor/antagonist; novel strategies; overexpression; solute; wasting

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.

血管内皮细胞的主要功能是调节和控制血管内皮细胞 血浆和血浆之间的水和溶质(小分子和大分子)的交换 间质液体，简而言之，控制血管的通透性。这个功能显然是“至关重要的”，即 对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。它也是 炎症中的防御机制的重要贡献者。而当 已经确定了涉及跨内皮交换的形态结构(即小凹， 内皮特异细胞器，如跨内皮通道、窗孔、囊泡-空泡 细胞器以及细胞间连接)，但小窝和细胞间连接除外 连接，很少或根本没有关于结构的分子组成的生化证据 它们的生物发生和调控。这项研究提案的主要目的是阐明 内皮窗生物发生的机制。除了它们对理解正常的 生理过程中的跨内皮细胞交换，这些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、慢性 炎症(病毒和细菌感染、移植排斥反应、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变 血管内皮细胞窗孔已经被证明是存在的。这些研究还有助于设计新的战略，以 药物和基因靶向到选定的微血管床。所采用的技术是细胞分离， 分级、生化分析、无细胞分析、转基因动物模型、细胞培养、 转染法、光镜和电子显微镜检查。