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CELLULAR BIOLOGY OF BRAIN MICROVESSELS

脑微血管的细胞生物学

基本信息

批准号：
3349642
负责人：
SAMI I HARIK
金额：
$ 21.91万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-09-30 至 1994-09-29
项目状态：
已结题

项目摘要

The goals of this proposal are to continue studies of the cellular mechanisms that underlie the complex functions of the brain circulation, and how this circulation is controlled to meet the changing and fastidious requirements of the brain. The endothelial cells of brain microvessels stand at the interface between the systemic circulation and nervous tissue and have a viral role in maintaining a stable environment for neuronal function and in preventing the entry of toxic substances into the brain. To accomplish this, the brain capillary endothelium is endowed with unique features, such as tight intercellular junctions, transporters for essential water-soluble molecules such as glucose and amino acids, and enzyme system that can effectively prevent the entry of some lipid-soluble toxins from blood to brain. The proposed experiments with employ complimentary biochemical, pharmacological, and ultrastructural techniques to study the brain microcirculation in vivo, and in preparations enriched with isolated microvessels, in vitro. The experiments will address the following subjects: (1) Receptors for peptide neurotransmitters and neuromodulators will be assessed in brain macro- and microvessels, and the mechanisms by which these agents mediate their effects will be investiagated. (2) Studies of the biochemical aspects of the blood-brain barrier that related to systemic 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) neurotoxicity. (3) To induce enzymes in brain microvessels that can metabolize MPTP, its analogs and other putative neurotoxins. (4) Synthesis of 18F-labeled MPTP analogs for use in investigating the neurobiology of MPTP toxicity by positron emission tomography. (5) Ultrastructural investigation of heterogenieties in the distribution of the glucose transporter and Na+,K+-ATPase in different brain regions and within the microvascular unit, by immunocytochemical methods. (6) Biochemical cellular and subcellular fractionation studies of brain microvessels. Better understanding of how the brain circulation functions may be prerequisite for appreciating the pathophysiology of this circulation. The proposed research may provide scientific bases for rational therapy of cerebrovascular disorders, metabolic encephalopathies and neurodegenerative disorders such as Parkinson's Disease.

该提案的目标是继续研究细胞大脑复杂功能的机制循环，以及如何控制该循环以满足大脑不断变化且挑剔的要求。这脑微血管的内皮细胞位于界面体循环和神经组织之间有病毒在维持神经元稳定环境中的作用功能并防止有毒物质进入脑。为了实现这一点，脑毛细血管内皮是具有独特的功能，例如紧密的细胞间连接点，重要水溶性分子的转运蛋白，例如如葡萄糖和氨基酸，以及可以有效阻止一些脂溶性毒素的进入血液到大脑。所提出的实验采用补充生化、药理学和超微结构体内研究大脑微循环的技术体外富含分离微血管的制剂。实验将解决以下主题：（1）肽神经递质和神经调节剂的受体将在大脑宏观和微血管中进行评估，及其机制将研究这些药物如何调节其影响。 (2)血脑屏障生化方面的研究与系统性1-甲基-4-苯基-1,2,3,6-相关四氢吡啶（MPTP）神经毒性。 (3)诱导酶在脑微血管中可以代谢 MPTP、其类似物和其他假定的神经毒素。 (4) 18F标记MPTP的合成用于研究 MPTP 毒性神经生物学的类似物通过正电子发射断层扫描。 (5)超微结构葡萄糖分布异质性的研究不同脑区的转运蛋白和Na+,K+-ATP酶通过免疫细胞化学方法在微血管单元内进行。 (6) 生化细胞和亚细胞分级分离研究脑微血管。更好地了解大脑循环功能可能是了解该疾病病理生理学的先决条件循环。拟议的研究可以提供科学依据合理治疗脑血管疾病、代谢性疾病脑病和神经退行性疾病，例如帕金森病。