Cellular and Molecular Mechanisms of Vascular Permeability

血管通透性的细胞和分子机制

基本信息

批准号：
7342057
负责人：
RADU VIRGIL STAN
金额：
$ 34.93万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-15 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7342057
关键词：
Acute Allergic Alzheimer&apos s Disease Animal Model Antibodies Atherosclerosis Automobile Driving Bacterial Infections Biochemical Biogenesis Biological Assay Biological Markers Biological Models Caveolae Cell Fractionation Cells Chronic Clathrin-Coated Vesicles Cloning Cultured Cells Data Databases Disease Disputes Drug Delivery Systems Electron Microscopy Endothelial Cells Endothelium FarGo Functional disorder Gene Targeting Genetically Modified Animals Goals Graft Rejection Growth In Situ Inflammation Intercellular Fluid Intercellular Junctions Knowledge Laboratories Lead Light Liquid substance Literature Mediating Mediation Microcirculatory Bed Microvascular Permeability Modeling Molecular Molecular Structure Morphology Organ Organelles Pathway interactions Permeability Pharmaceutical Preparations Phenotype Physiological Physiological Processes Physiology Plasma Process Proteins Range Rate Reagent Regulation Research Research Personnel Research Proposals Respiratory Diaphragm Role Site Structure Subcellular structure System Techniques Testing Tissues Transfection Transgenic Mice Travel Tumor Angiogenesis Vascular Endothelium Vascular Permeabilities Vesicle Viral Water Work base caveolin 1 design experience human disease in vivo innovation macromolecule novel programs solute transcytosis vascular bed

项目摘要

The main function of the vascular endothelium is the mediation and control of the transendothelialexchanges of water and solutes (both small and large molecules) between blood plasma and theinterstitial fluid, in short the control of vascular permeability. This function is obviously "vital", being critical for normal growth, maintainance and survival of all the cells from all tissues and organs . 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), 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 role of endothelial caveolae and their associated stomatal diaphragms in the transendothelial transport physiology. The findings 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 such as tumor angiogenesis, atherosclerosis, acute and chronic inflammation (both viral and bacterial infections, transplant rejection, allergic encephalomyelytis, Alzheimer disease) where such 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, biochemical assays, cell free-assays, in-vivo transport studies, genetically modified animal models, cell culture, transfections, light and electron microscopy.

血管内皮的主要功能是介导和控制跨内皮交换简而言之，血浆和间质液之间的水和溶质（小分子和大分子）血管通透性的控制。这个功能显然是“至关重要的”，对于正常生长至关重要，所有组织和器官的所有细胞的维持和存活。而形态结构已确定参与跨内皮交换（即细胞膜窝、内皮特异性细胞器）例如跨内皮通道、窗孔、囊泡-液泡细胞器以及细胞间连接），关于所涉及结构的分子组成、它们的结构的生化证据很少甚至没有生物发生和调节。本研究计划的主要目标是阐明内皮细胞的作用跨内皮运输生理学中的小窝及其相关的气孔隔膜。研究结果还将记录跨内皮运输的一个新颖方面，即其可能性和方式调制（传输速率和成分）。除了影响正常的理解之外跨内皮转运的生理过程，该数据可进一步用于研究多种人类疾病的病理生理学，如肿瘤血管生成、动脉粥样硬化、急性和慢性疾病炎症（病毒和细菌感染、移植排斥、过敏性脑脊髓炎、阿尔茨海默病疾病），这种调节已被证明发生。这些研究还可以提供新颖的可用于设计药物策略的运输相关内皮特异性分子标记以及对选定的微血管床进行基因靶向。所采用的技术是细胞分级分离、生化测定、无细胞测定、体内转运研究、转基因动物模型、细胞培养、转染、光学和电子显微镜。