Mechanisms and therapeutic targets of neurovascular injury in hyperglycemic stroke

尽管30%的中风患者患有糖尿病，超过50%的患者出现中风后高血糖(HG)，但 血糖正常化在急性卒中环境中的临床益处是有争议的，因为 低血糖症。此外，糖尿病和高血压都与较差的神经预后有关。 再灌注治疗有疗效，并加重血管并发症。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 确定合适的药物靶点，以帮助发现新的和临床适用的治疗方法以改善 中风结局。此应用的目的是确定内皮-TXNIP在高血糖中的作用 中风导致的神经血管损伤。硫氧还蛋白相互作用蛋白(TXNIP)，主要的细胞内调节因子 氧化还原/葡萄糖诱导的应激和炎症，现在已知在中风中上调，呈现出一种 前景看好的治疗靶点。在初步研究中，我们已经证明HG小鼠有更高的TXNIP 与野生型(WT)对照组相比，栓塞性卒中后的表达和出血增加。这些 令人振奋的发现表明，TXNIP是一种有前途的脑卒中治疗靶点。然而， 关于血管TXNIP在炎症反应中的具体作用存在明确的认识空白 缺血再灌注(TPA)损伤反应。因此，我们的中心假设是HG/再灌流- 诱导的TXNIP表达通过激活NLRP3-炎症体、血管 卒中后血管内皮细胞生长因子(VEGF)和基质金属蛋白酶(MMP)。这一假设将是 目的1：验证HG通过激活血管紧张素转运蛋白而加重再灌注损伤的假设 TXNIP-NLRP3卒中后炎性小体。目的2：验证高血糖导致中风的假说 TXNIP触发血管内皮生长因子和基质金属蛋白酶介导的神经血管损伤。目标3：检验一部小说 TXNIP抑制剂可减轻高血糖卒中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)确定由以下因素引起的高血糖中风- TXNIP是NLRP3炎症体形成的关键介质，以及(2)证实高血糖卒中 诱导的TXNIP-NLRP3利用内皮细胞特异性触发血管内皮生长因子和基质金属蛋白酶介导的神经血管损伤 (EC)-TXNIP-/-小鼠，NLRP3、MMP9/2和血管内皮生长因子抑制剂，静脉注射tPA(1.5h)。(3) 我们的研究将首次使用新创建的TXNIP和NLRP3的特异性抑制剂来解决 TXNIP的治疗抑制是否会改善缺血半暗带的长期恢复和范围 通过使用磁共振弥散张量成像(DTI)在栓塞性卒中。这些研究可能会产生深远的影响 血管血栓素NIP作为继发性损伤的关键介质的翻译意义 为HG/糖尿病合并卒中神经血管损伤的治疗干预提供新的靶点。

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.