Mitochondrial Carbonic Anhydrases and Diabetic Blood-Brain Barrier Disruption

线粒体碳酸酐酶和糖尿病血脑屏障破坏

基本信息

  • 批准号:
    8420518
  • 负责人:
  • 金额:
    $ 30.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-02-01 至 2015-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Diabetes mellitus is associated with deterioration of the brain's microvasculature and the blood-brain barrier (BBB) that it forms. The BBB prevents the unrestricted leakage of plasma proteins into the brain. The vascular BBB is physically formed by specially modified brain endothelial cells (BECs), but other cell types interact with it to form the neurovascular unit (NVU). Pericytes in particular are important in maintaining BBB function in the face of glycemic insult. We have shown in vitro that the insulin transporter is lost in the face of high glucose concentrations unless BECs are co-cultured with pericytes; astrocyte co-culture does not preserve BEC insulin transporter function. However, pericytes are themselves susceptible to glucose toxicity and the accompanying oxidative stress. Work with retinal pericytes and the blood-retinal barrier (BRB) shows that hyperglycemia induces apoptosis in retinal pericytes; with pericyte loss the BRB deteriorates. Mitochondrial carbonic anhydrases (CAs) are important in the generation of reactive oxygen species (ROS) and the subsequent oxidative stress that arises and is accelerated during hyperglycemia. In brief, mitochondrial CAs generate mitochondrial bicarbonate that is necessary for the oxidative catabolism of glucose, the major source of ROS. Hyperglycemia accelerates this process, increasing production of ROS. Blocking mitochondrial CAs shuttles pyruvate through anaerobic metabolism and so prevents excessive ROS production. We hypothesize that inhibition of mitochondrial carbonic anhydrases (CAs) will protect pericytes and BECs from ROS induced apoptosis and slow the development of disruption of the BBB in STZ-induced diabetes. Wewill test this hypothesis in two specific aims. SA1 will measure oxidative stress induced by high glucose media and the resulting mitochondrial leakage and apoptosis in primary cultures of brain pericytes and BEC isolated from mitochondrial CA KO & WT mice and in pericytes and BEC that overexpress CA or are treated with clinically used CA inhibitors. SA 2 will measure in diabetic and control mice BBB disruption and oxidative stress in BEC from CA KO mice, WT mice, and mice treated with the CA inhibitors of SA1.
描述(由申请人提供):糖尿病与脑微血管系统及其形成的血脑屏障(BBB)的恶化有关。血脑屏障防止血浆蛋白不受限制地渗漏到大脑中。血管血脑屏障由特殊修饰的脑内皮细胞(BEC)物理形成,但其他细胞类型与它相互作用形成神经血管单位(NVU)。周细胞在面对血糖损伤时维持BBB功能尤其重要。我们已经在体外研究表明,胰岛素转运蛋白在面对高浓度葡萄糖时会丢失,除非BEC与周细胞共培养;星形胶质细胞共培养不会保留BEC胰岛素转运蛋白功能。然而,周细胞本身对葡萄糖毒性和伴随的氧化应激敏感。对视网膜周细胞和血视网膜屏障(BRB)的研究表明,高血糖诱导视网膜周细胞凋亡;随着周细胞损失,BRB恶化。线粒体碳酸酐酶(CA)在活性氧(ROS)的产生以及随后在高血糖期间产生并加速的氧化应激中是重要的。简而言之,线粒体CA产生线粒体碳酸氢盐,这对于葡萄糖的氧化催化是必需的,葡萄糖是ROS的主要来源。Hyperoxia加速了这一过程,增加了ROS的产生。阻断线粒体CA使丙酮酸穿梭通过厌氧代谢,从而防止过量的ROS产生。我们假设,线粒体碳酸酐酶(CA)的抑制将保护周细胞和BEC从ROS诱导的细胞凋亡和减缓发展的破坏血脑屏障STZ诱导的糖尿病。我们将在两个具体目标中检验这一假设。SA 1将测量由高葡萄糖培养基诱导的氧化应激以及从线粒体CA KO & WT小鼠分离的脑周细胞和BEC的原代培养物中以及过表达CA或用临床使用的CA抑制剂处理的周细胞和BEC中产生的线粒体渗漏和细胞凋亡。SA 2将测量糖尿病小鼠和对照小鼠中的BBB破坏和来自CA KO小鼠、WT小鼠和用SA 1的CA抑制剂处理的小鼠的BEC中的氧化应激。

项目成果

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WILLIAM A BANKS其他文献

WILLIAM A BANKS的其他文献

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{{ truncateString('WILLIAM A BANKS', 18)}}的其他基金

Mechanisms of Blood-brain Barrier Disruption in Type II Diabetes
II 型糖尿病血脑屏障破坏的机制
  • 批准号:
    9110653
  • 财政年份:
    2016
  • 资助金额:
    $ 30.98万
  • 项目类别:
Modulation of IgG blood-brain barrier permeability by surface-accessible glycan moieties
通过表面可及的聚糖部分调节 IgG 血脑屏障通透性
  • 批准号:
    8872573
  • 财政年份:
    2015
  • 资助金额:
    $ 30.98万
  • 项目类别:
Modulation of IgG blood-brain barrier permeability by surface-accessible glycan moieties
通过表面可及的聚糖部分调节 IgG 血脑屏障通透性
  • 批准号:
    9069723
  • 财政年份:
    2015
  • 资助金额:
    $ 30.98万
  • 项目类别:
Intranasal Insulin in a Mouse Model of Alzheimer's Disease
阿尔茨海默病小鼠模型中的鼻内胰岛素
  • 批准号:
    9514755
  • 财政年份:
    2014
  • 资助金额:
    $ 30.98万
  • 项目类别:
Intranasal Insulin in a Mouse Model of Alzheimer's Disease
阿尔茨海默病小鼠模型中的鼻内胰岛素
  • 批准号:
    8760193
  • 财政年份:
    2014
  • 资助金额:
    $ 30.98万
  • 项目类别:
Intranasal Insulin in a Mouse Model of Alzheimer's Disease
阿尔茨海默病小鼠模型中的鼻内胰岛素
  • 批准号:
    8919201
  • 财政年份:
    2014
  • 资助金额:
    $ 30.98万
  • 项目类别:
Intranasal Insulin in a Mouse Model of Alzheimer's Disease
阿尔茨海默病小鼠模型中的鼻内胰岛素
  • 批准号:
    9050620
  • 财政年份:
    2014
  • 资助金额:
    $ 30.98万
  • 项目类别:
Mitochondrial Carbonic Anhydrases and Diabetic Blood-Brain Barrier Disruption
线粒体碳酸酐酶和糖尿病血脑屏障破坏
  • 批准号:
    8213409
  • 财政年份:
    2011
  • 资助金额:
    $ 30.98万
  • 项目类别:
Mitochondrial Carbonic Anhydrases and Diabetic Blood-Brain Barrier Disruption
线粒体碳酸酐酶和糖尿病血脑屏障破坏
  • 批准号:
    8604388
  • 财政年份:
    2011
  • 资助金额:
    $ 30.98万
  • 项目类别:
Mitochondrial Carbonic Anhydrases and Diabetic Blood-Brain Barrier Disruption
线粒体碳酸酐酶和糖尿病血脑屏障破坏
  • 批准号:
    8041786
  • 财政年份:
    2011
  • 资助金额:
    $ 30.98万
  • 项目类别:

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