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
• 负责人: WILLIAM A BANKS
• 金额: $ 17.58万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110653
• 关键词: Address; Affect; Albumins; Apoptosis; Appearance; Applications Grants; Area; Arteries; Astrocytes; Attenuated; Bicarbonates; Blindness; Blocking Antibodies; Blood; Blood - brain barrier anatomy; Brain; Brain region; Carbonic Anhydrase Inhibitors; Cell Respiration; Cells; Chronic; Communication; Corpus striatum structure; Data; Deterioration; Development; Diabetes Mellitus; Diabetic mouse; Diet; Disease; Disease Progression; End stage renal failure; Extravasation; Functional disorder; Future; Glucose; Glutathione Disulfide; Hexosamines; High Fat Diet; Hippocampus (Brain); Hyperglycemia; Impaired cognition; Insulin; Insulin-Dependent Diabetes Mellitus; Isoprostanes; Kidney Diseases; Kidney Glomerulus; Label; Leptin; Measures; Metabolism; Midbrain structure; Mitochondria; Modeling; Mus; Myocardial Infarction; Neuraxis; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Occipital lobe; Oxidative Stress; Parietal Lobe; Pathology; Pathway interactions; Pattern; Peptides; Pericytes; Peripheral Nerves; Permeability; Plasma Proteins; Production; Pyruvate; Reactive Oxygen Species; Retina; Retinal Diseases; Role; Side; Streptozocin; Stroke; Sucrose; Technetium 99m; Testing; Thalamic structure; United States National Institutes of Health; Vascular blood supply; Warburg Effect; aerobic glycolysis; brain endothelial cell; brain tissue; cell type; cerebral microvasculature; cognitive function; design; diabetic; diabetic patient; frontal lobe; high risk; insight; limb amputation; macrovascular disease; microvascular pathology; mouse model; neurogenesis; polyol; prevent; protective effect; public health relevance; receptor; topiramate

 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（由申请人提供）：所有形式的糖尿病都以慢性高血糖为特征，导致多种微血管和大血管病变的发展，在视网膜、肾小球和周围神经中很明显，导致失明、死亡。糖尿病患者患心肌梗塞的风险较高。 由于影响向这些区域供血的动脉的加速大血管疾病而导致中风和截肢，糖尿病也与导致血脑屏障（BBB）功能障碍和破坏的脑微血管变化有关。 BBB 是大脑和血液之间的调节界面，可防止血浆蛋白不受限制地渗漏至中枢神经系统 (CNS)，并在糖尿病中发挥营养、稳态和沟通作用。氧化应激 (OxSt) 和活性氧 (ROS) 增加 这是因为使用线粒体碳酸酐酶抑制剂 (mCAI) 导致葡萄糖氧化代谢增加。我们的初步研究表明，限制氧化代谢和 ROS 的产生，从而驱动丙酮酸进行有氧糖酵解以产生 ATP，而不产生 ROS。研究小组证明，i) STZ 诱导的糖尿病会导致 BBB 破坏，ii) 超微结构研究显示大脑周细胞损失和星形胶质细胞回缩，这是维持 BBB 的两种细胞类型，iii) 托吡酯（一种线粒体碳酸酐酶）治疗在我们使用 STZ 诱导的 I 型糖尿病小鼠模型的研究中，胰岛素和瘦素水平较低，BBB 破坏发生在五个大脑区域：额叶皮质、相比之下，CD-1 小鼠的饮食诱发肥胖 (DIO) 模型的初步结果显示，其中胰岛素和瘦素水平较高，血脑屏障受到破坏。没有发生在这五个区域，但确实发生在海马和纹状体中，我们发现瘦素或胰岛素对血脑屏障具有保护作用，但已知它们会诱导神经发生的区域除外。这项研究的成功完成将为研究 II 型糖尿病患者大脑微血管系统的恶化提供宝贵的见解。此处收集的数据将为 NIH R01 拨款申请提供初步数据，以进一步了解该领域。 。