Mechanisms of Blood-brain Barrier Disruption in Type II Diabetes

II 型糖尿病血脑屏障破坏的机制

基本信息

项目摘要

 DESCRIPTION (provided by applicant): All forms of diabetes mellitus are characterized by chronic hyperglycemia resulting in the development of a number of microvascular and macrovascular pathologies. Microvascular pathologies are apparent in the retina, renal glomerulus, and peripheral nerve, resulting in blindness, end-stage renal disease, and a variety of debilitating neuropathies. Also, diabetic patients are at higher risk for myocardial infarction, stroke, and limb amputation because of accelerated macrovascular disease affecting arteries that supply blood to these regions. Diabetes is also associated with changes in brain microvasculature leading to dysfunction and disruption of the blood-brain barrier (BBB). These changes are correlated with a decline in cognitive function. The BBB is a regulatory interface between brain and blood, preventing the unrestricted leakage of plasma proteins into the central nervous system (CNS) and performing nutritive, homeostatic, and communication roles. In diabetes BBB damage is associated with increased oxidative stress (OxSt) and reactive oxygen species (ROS). This occurs because of the increased oxidative metabolism of glucose caused by hyperglycemia. Decreasing the production of bicarbonate (HCO3-) with the use of a mitochondrial carbonic anhydrase inhibitor (mCAI) limits oxidative metabolism and the production of ROS, which drives pyruvate to undergo aerobic glycolysis to produce ATP without producing ROS. Preliminary studies by our group have demonstrated that i) STZ-induced diabetes results in BBB disruption, ii) ultrastructural studies show a loss of brain pericytes and retraction of astrocytes, the two cell types that maintain the BBB, and iii) treatment with topiramate, a mitochondrial carbonic anhydrase inhibitor, attenuated the effects. In our studies using an STZ- induced mouse model of Type I diabetes, where insulin and leptin levels are low, BBB disruption occurred in five brain regions: frontal cortex, occipital cortex, parietal cortex, midbrain, and thalamus. In contrast, preliminary results in a diet induced obesity (DIO) model of Type II diabetes in the outbred strain of CD-1 mice, where insulin and leptin levels are high, BBB disruption did not occur in those five regions but did occur in the hippocampus and striatum. We hypothesize that either leptin or insulin exerted protective effects at the BBB except in those regions where they are known to induce neurogenesis, such as the hippocampus, and hence increased metabolism. Successful completion of this study will provide valuable insight into studying the deterioration of brain microvasculature in type II diabetes mellitus. Data collected here will provide preliminary data for an NIH R01 grant application to further our understanding of this field.
 描述(由申请方提供):所有形式的糖尿病的特征均为慢性高血糖症,导致许多微血管和大血管病变的发展。微血管病变在视网膜、肾小球和外周神经中是明显的,导致失明、终末期肾病和各种使人衰弱的神经病变。此外,糖尿病患者患心肌梗死的风险更高, 中风和截肢,因为加速的大血管疾病影响了向这些区域供血的动脉。糖尿病还与脑微血管系统的变化相关,导致血脑屏障(BBB)的功能障碍和破坏。这些变化与认知功能下降有关。血脑屏障是大脑和血液之间的调节界面,防止血浆蛋白不受限制地泄漏到中枢神经系统(CNS)中,并发挥营养、稳态和通讯作用。在糖尿病中,BBB损伤与氧化应激(OxSt)和活性氧(ROS)增加有关。这是由于高血糖引起的葡萄糖氧化代谢增加所致。使用线粒体碳酸酐酶抑制剂(mCAI)减少碳酸氢盐(HCO 3-)的产生限制了氧化代谢和ROS的产生,这驱使丙酮酸进行有氧糖酵解以产生ATP而不产生ROS。我们小组的初步研究表明,i)STZ诱导的糖尿病导致BBB破坏,ii)超微结构研究显示脑周细胞的损失和星形胶质细胞的收缩,这两种细胞类型维持BBB,和iii)用托吡酯(一种线粒体碳酸酐酶抑制剂)治疗,减弱了这种作用。在我们使用STZ诱导的I型糖尿病小鼠模型的研究中,其中胰岛素和瘦素水平低,BBB破坏发生在五个脑区域:额叶皮质、枕叶皮质、顶叶皮质、中脑和丘脑。相比之下,在CD-1小鼠的远交品系中的II型糖尿病的饮食诱导的肥胖(DIO)模型中的初步结果,其中胰岛素和瘦素水平高,BBB破坏未发生在这五个区域中,但发生在海马体和纹状体中。我们假设瘦素或胰岛素在BBB发挥保护作用,除了在那些已知它们诱导神经发生的区域,如海马,因此增加代谢。这项研究的成功完成将为研究II型糖尿病患者脑微血管的恶化提供有价值的见解。这里收集的数据将为NIH R 01拨款申请提供初步数据,以进一步了解这一领域。

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

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:
    $ 17.58万
  • 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:
    $ 17.58万
  • 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:
    $ 17.58万
  • 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:
    $ 17.58万
  • 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:
    $ 17.58万
  • 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:
    $ 17.58万
  • 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:
    $ 17.58万
  • 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:
    8420518
  • 财政年份:
    2011
  • 资助金额:
    $ 17.58万
  • 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:
    $ 17.58万
  • 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:
    $ 17.58万
  • 项目类别:

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