MOLECULAR PATHOLOGY OF BLOOD-BRAIN BARRIER BREAKDOWN

血脑屏障破坏的分子病理学

• 批准号: 3398097
• 负责人: HAROLD KOENIG
• 金额: $ 13.22万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-12-01 至 1987-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3398097
• 关键词: aspirin; astrocytes; blood brain barrier; brain circulation; brain edema; calcium; capillary; cardiovascular pharmacology; cyclic AMP; decarboxylase inhibitor; deoxyglucose; dexamethasone; eicosanoid metabolism; electrocorticography; electron microscopy; enzyme induction /repression; experimental brain lesion; histochemistry /cytochemistry; ion transport; molecular pathology; ornithine decarboxylase; phase contrast microscopy; pinocytosis; polyamines; radiotracer; tissue /cell culture; vascular endothelium permeability; verapamil

This research project will continue studies on the molecular & cellular mechanisms of blood-brain barrier (BBB) breakdown. The BBB, which normally restricts the entry of diverse polar molecules into the brain, reflects the unique structure of the endothelial cells lining the cerebral microvessels. These cells are joined by tightly sealed junctions, & contain few pinocytotic vesicles & no fenestrae. Vasogenic brain edema, the most commonly encountered form of brain edema, features a disruption of BBB function associated with intense pinocytosis & transcytosis of blood-borne substances into the brain extracellular space, & possibly enhanced transport of other substrated (Na+, K+, CA2+, glucose, amino acids) by specific carrier-mediated transport systems in BBB. Previous studies in this laboratory established that BBB breakdown induced by cold injury is associated with a rapid biphasic incease in polyamines & their rate-limiting synthetic enzyme ornithine decarboxylase (ODC) in rat cerebral parenchyma and microvessels. This polyamine synthesis is essential for BBB breakdown and the increased transcytosis of horseradish peroxidase, as it is abolished by the ODC inhibitor Alpha-difluoromethylornithine (DFMO), and putrescine nullifies the effects of DFMO. Stimulation of ODC activity and the associated BBB breakdown induced by freeze injury apparently involves CA2+ transport and prostaglandin synthesis as both are suppressed by verapamil, dexamethasone and aspirin. The specific aims are to study in injured cerebral microvessel endothelium: (1) the mechanisms underlying the primary (posttranslational?) and secondary (transcriptional?) regulation of ODC; (2) changes in 45Ca2+ influx and efflux, and free cytosolic CA2+ levels and their polyamine-dependence: (3) changes in rates of transcytosis and transport of 22Na+, 86Rb+, 3H-deoxyglucose, 3H-Alpha-aminoisobutyrate, and their polyamine- and Ca2+ dependence; (4) quantiative morphometry of ultrastructural and cytochemical changes in structures mediating transcytosis, and relative volumes of cytolasm, nucleus, mitochondria, endoplasmic reticulum and Golgi; (5) role of polyamines in the astrocytic response to freeze-injury (pinocytosis and lysosomal sequestration of HRP, hypertrophy, hyperplasia); (6) polyamine-dependence of focal and generalized abnormalities in EEG activity and glucose utilization developing in brain after freeze injury. These aims will be studied in three systems: in situ in rat cerebrum after freeze and osmotic injury; in isolated cerebral microvessels; and in cultured cerebral microvessel endothelium.

该研究项目将继续研究分子和细胞 血脑屏障（BBB）崩溃的机制。 BBB，通常 限制了各种极性分子进入大脑的进入，反映了 内皮细胞的独特结构 微量花序。 这些细胞通过紧密密封的连接连接，＆ 含有很少的皮细胞囊泡，没有fenestrae。 血管生成脑水肿， 最常见的脑水肿形式，特征是 BBB功能与强烈的性腺毒性和转胞膜相关的功能 血液传播物质进入大脑细胞外空间，可能 增强其他底座的运输（Na+，K+，Ca2+，葡萄糖，氨基 酸）通过BBB中的特定载体介导的运输系统。 以前的 该实验室的研究确定，寒冷引起的BBB分解 损伤与多胺及其中的双相性疾病及其快速有关 大鼠中限速合成酶鸟氨酸脱羧酶（ODC） 大脑实质和微血管。 这种多胺合成是 BBB崩溃至关重 过氧化物酶，因为它被ODC抑制剂废除 α-二氟甲基氨酸氨酸（DFMO），并腐烂使效果无效 DFMO。 刺激ODC活性和相关的BBB分解 冻伤诱导的显然涉及CA2+运输和 前列腺素合成，因为两者都被维拉帕米，地塞米松抑制 和阿司匹林。 具体的目的是研究受伤的脑 微血管内皮：（1）主要的机制 （翻译后？）和ODC的次要（转录？）调节； （2）45CA2+涌入和外排的变化，以及游离的胞质Ca2+水平和 它们的多胺依赖性：（3）转胞病率的变化和 22NA+，86RB+，3H-脱氧葡萄糖，3H-α-氨基丁酸酯的运输和 他们的多胺和Ca2+依赖性； （4）定量形态测定法 介导的超微结构和细胞化学变化 胞胞菌病和细胞肿瘤，核，线粒体，线粒体的相对体积 内质网和高尔基体； （5）多胺在星形细胞中的作用 对冻伤的响应（HRP的性腺毒性和溶酶体隔离， 肥大，增生）； （6）焦点和焦点的多胺依赖性 EEG活性和葡萄糖利用率的普遍异常 冻伤后在大脑中发育。 这些目标将在 三个系统：冻结和渗透损伤后的大鼠大脑原位；在 孤立的脑微血管；并在培养的脑微血管中 内皮。