Mechanisms and therapeutic targets of neurovascular injury in hyperglycemic stroke

高血糖脑卒中神经血管损伤的机制及治疗靶点

• 批准号: 9468911
• 负责人: Tauheed Ishrat
• 金额: $ 33.25万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9468911
• 关键词: Acute; Address; Adult; Alteplase; Attenuated; Avastin; Behavioral; Blood - brain barrier anatomy; Blood Vessels; CASP3 gene; Cerebrovascular system; Cessation of life; Chronic; Clinical; Coculture Techniques; Couples; Data; Development; Diabetes Mellitus; Diffusion Magnetic Resonance Imaging; Drug Targeting; Edema; Extravasation; Future; Gelatinase B; Glucose; Goals; Hemorrhage; Hyperglycemia; Hyperglycemic Mice; Hypoglycemia; Hypoxia; Immune response; Infarction; Inflammasome; Inflammation; Inflammatory Response; Injury; Interleukin-1 beta; Intravenous; Ischemia; Ischemic Penumbra; Ischemic Stroke; Knock-out; Knowledge; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Modeling; Motor; Mouse Protein; Mus; Neurological outcome; Neurons; Outcome; Oxidation-Reduction; Pathway interactions; Patients; Process; Protein Inhibition; Publishing; Recovery; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Risk; Role; SB 3CT compound; Severities; Signal Transduction; Streptozocin; Stress; Stroke; TXNIP gene; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; United States; Up-Regulation; Vascular Endothelial Growth Factors; Wild Type Mouse; acute stroke; brain endothelial cell; clinical application; cognitive function; diabetic; disability; gene therapy; glucose metabolism; improved; inhibitor/antagonist; neuron loss; neurovascular; neurovascular injury; new therapeutic target; novel; novel therapeutics; post stroke; protein expression; stroke recovery; stroke treatment; therapeutic target; therapy development; treatment effect; vascular contributions; vascular inflammation

Although 30% of patients with stroke are diabetic, and over 50% develop post-stroke hyperglycemia (HG), the clinical benefit of glucose normalization in the acute stroke setting is problematic controversial due to the risk of hypoglycemia. Moreover, both diabetes and HG are associated with worse neurological outcomes, lower reperfusion therapies efficacy, and aggravated vascular complications. Hence, there is an urgent need to identify novel targets for the development of treatments that mitigate these risks. Our long-term goal is to identify suitable drug targets to aid in the discovery of novel and clinically applicable therapies for improving stroke outcome. The objective of this application is to determine the role of endothelial-TXNIP in hyperglycemic stroke-induced neurovascular damage. Thioredoxin-interacting protein (TXNIP), a major intracellular regulator of redox/ glucose induced stress and inflammation, now known to be upregulated in stroke, presents a promising therapeutic target. In preliminary studies, we have demonstrated that HG mice have higher TXNIP expression and increased hemorrhage after an embolic stroke compared to wild type (WT) controls. These exciting findings have suggested that TXNIP as a promising therapeutic target in cerebral stroke. However, there are definite knowledge gaps concerning the specific contribution of vascular TXNIP to the inflammatory response in ischemia and reperfusion (tPA) injury. Therefore, our central hypothesis is that HG/ reperfusion- induced TXNIP expression sustains neurovascular injury through activation of NLRP3-inflammasome, vascular endothelial growth factor (VEGF), and matrix metalloproteinase (MMP) after stroke. This hypothesis will be tested in three specific: Aim 1: Test the hypothesis that HG exacerbates reperfusion injury by activating the TXNIP-NLRP3 inflammasome after stroke. Aim 2: Test the hypothesis that hyperglycemic stroke-induced TXNIP triggers VEGF and MMP mediated neurovascular damage. Aim 3: Test the hypothesis that a novel TXNIP inhibitor attenuates hyperglycemic stroke-induced neurovascular damage and functional deficits. Expected outcomes of the proposed research include: (1) Identification of hyperglycemic stroke induced- TXNIP as a key mediator of NLRP3 inflammasome formation, and (2) demonstration that hyperglycemic stroke induced-TXNIP-NLRP3 triggers VEGF and MMP-mediated neurovascular damage, using endothelial specific (EC)-TXNIP-/- mice, a specific NLRP3, MMP-9/2 and VEGF inhibitors, and reperfusion with IV-tPA (1.5 h). (3) Our study will be the first to use of the newly created specific inhibitors for TXNIP and NLRP3 to address whether therapeutic inhibition of TXNIP will improve long-term recovery and extent of the ischemic penumbra by using MRI-diffusion tensor imaging (DTI) in an embolic stroke. These studies may have far-reaching translational implications as the identification of vascular TXNIP, as key mediators of secondary injury will provide novel targets for therapeutic intervention in HG/diabetes associated neurovascular injury in stroke.

尽管30％的中风患者患有糖尿病患者，超过50％的中风后高血糖（HG），但 急性中风环境中葡萄糖归一化的临床益处是有争议的，因为 低血糖。此外，糖尿病和HG都与较差的神经系统结局有关，较低 再灌注疗法功效和加重的血管并发症。因此，迫切需要 确定新的目标，以开发减轻这些风险的治疗方法。我们的长期目标是 确定合适的药物靶标，以帮助发现新颖和临床适用的疗法以改善 中风结果。该应用的目的是确定内皮-TXNIP在高血糖中的作用 中风引起的神经血管损伤。硫氧还蛋白相互作用蛋白（TXNIP），一种主要的细胞内调节剂 氧化还原/葡萄糖诱导的应激和炎症的炎症，现在已知在中风中上调，呈现A 有希望的治疗靶标。在初步研究中，我们已经证明HG小鼠具有较高的TxNIP 与野生型（WT）对照相比，栓塞中风后的表达和出血增加。这些 令人兴奋的发现表明，TXNIP是大脑中风中有希望的治疗靶标。然而， 关于血管TXNIP对炎症的具体贡献的一定知识差距 缺血和再灌注（TPA）损伤的反应。因此，我们的核心假设是HG/ REPEREREREFUSION- 诱导的TXNIP表达通过激活NLRP3-炎症，血管造成神经血管损伤 中风后内皮生长因子（VEGF）和基质金属蛋白酶（MMP）。这个假设将是 以三个特定的特定测试：目标1：测试以下假设，即HG通过激活该假设加剧了再灌注损伤 中风后TXNIP-NLRP3炎性体。 AIM 2：检验高血糖中风诱导的假设 TXNIP触发VEGF和MMP介导的神经血管损伤。目标3：检验一个小说的假设 TXNIP抑制剂减弱了高血糖中风引起的神经血管损伤和功能缺陷。 拟议研究的预期结果包括：（1）鉴定高血糖中风引起的 - txnip作为NLRP3炎性体形成的关键介体，（2）证明高血糖中风 使用内皮特异 （ec）-txnip - / - 小鼠，特定的NLRP3，MMP-9/2和VEGF抑制剂，并用IV-TPA再灌注（1.5 h）。 （3） 我们的研究将是首次使用新创建的TXNIP和NLRP3的特定抑制剂来解决 TXNIP的治疗性抑制是否会改善长期恢复和缺血性半衰期的程度 通过在栓塞中风中使用MRI扩散张量成像（DTI）。这些研究可能有深远的角度 翻译含义是鉴定血管TXNIP的识别，作为继发性损伤的关键介体 为中风中与HG/糖尿病相关的HG/糖尿病的治疗干预提供了新的靶标。