Cerebral arteriole structure/function in diabetic ischemic brain injury

超过7%的美国人口和20%的退伍军人患有糖尿病， 急性缺血性卒中的风险更高，但也遭受不利的卒中结局， 复苏组织型纤溶酶原激活剂（tPA）再灌注治疗是目前治疗缺血性脑卒中的唯一方法; 然而，这种治疗增加了脑出血（出血性转化，HT）的风险。 糖尿病人在这种高风险的疾病中，开发新的治疗策略的关键障碍是 糖尿病患者的主要问题是缺乏对出血严重程度如何影响卒中结局和糖尿病恢复的了解。 此更新申请的具体目标是通过定义影响来解决这一关键障碍 以及糖尿病缺血性卒中后HT损害神经血管修复的机制。在过去 我们报告说，a）在2型糖尿病患者中， B）叠加在这种病理学上的再灌注损伤放大了HT和神经系统损伤 缺乏而不增加梗死面积，和c）在没有再灌注的情况下，没有HT，没有差异 在对照组和糖尿病动物之间的功能结果。这些新的结果指导我们识别大脑 血管和HT作为糖尿病缺血性卒中的治疗靶点。危险相关分子模式 细胞死亡后释放的细胞内分子DAMP是一个新兴的概念，涉及细胞死亡的过程。 通过Toll样受体（TLR）激活先天免疫系统。在此基础上，中央 有一种假说认为，脑出血、瘀点或占位损害神经血管恢复 并通过过量铁激活TLR-4（一种新的DAMP）导致糖尿病的结局。实现我们 总体目标，目标1将测试的假设，即使是瘀点非占位HT损害 神经血管恢复性修复和糖尿病的神经功能缺损。目标2将检验假设 糖尿病患者HT水平升高导致的铁沉积损害了神经血管的可塑性， 缺血性卒中的结局。目的3将检验HT刺激TLR 4信号传导的假设， 糖尿病缺血性脑卒中后炎症恶化的修复和恢复。从我们的 翻译研究将产生以下结果：a）我们将挑战现有的范式， 占位性HT的结果表明，任何出血进入大脑是有害的， 损害血管和神经元修复，B）我们将产生新的和重要的数据， 糖尿病如何通过使用各种动物组合减弱神经元和内皮修复过程 糖尿病或中风模型，以概括临床状况，以及c）我们将确定铁作为新的DAMP 并显示铁螯合和/或下游TLR 4抑制是中风中有希望的治疗靶点， 治疗/康复。该项目将对中风研究、人类健康和VA使命产生重大影响 因为它将1）确定神经血管保护和恢复策略，以改善卒中结局，2） 推进我们对脑血管在卒中修复中的作用的认识，以及3）提供具体的 关于糖尿病中风恢复的信息，每年800，000例中风中有30%以上发生 受害者我们已经准备好迎接这一挑战，因为我们已经与VA科学家建立了合作关系 为该提案的目标提供了支持。

More than 7% of the US population and 20% of our veterans who have diabetes are not only at a 2 to 6-fold higher risk for having acute ischemic stroke but also suffer from unfavorable stroke outcome and poor recovery. Reperfusion therapy with tissue plasminogen activator (tPA) is the only therapy for ischemic stroke; however, this treatment increases the risk of bleeding into the brain (hemorrhagic transformation, HT) of diabetics. A critical barrier to progress in the development of new therapeutic strategies in this high-risk population is the lack of understanding how bleeding severity impacts stroke outcome & recovery in diabetes. The specific objective of this renewal application is to address this critical barrier by defining the impact and mechanisms by which HT impairs neurovascular repair after ischemic stroke in diabetes. During the past funding period we reported that a) there is robust pathological neovascularization of the brain in type 2 diabetes, b) a reperfusion injury superimposed on this pathology amplifies HT and worsens neurological deficits without increasing infarct size, and c) in the absence of reperfusion, there is no HT and no difference in functional outcome between control and diabetic animals. These novel results guided us to identify cerebral vasculature and HT as a therapeutic target in diabetic ischemic stroke. Danger-associated molecular patterns (DAMPs), intracellular molecules released upon cell death, is an emerging concept that is involved in the activation of the innate immune system via toll-like receptors (TLRs). Based on this foundation, the central hypothesis is that bleeding into the brain, petechial OR space-occupying, impairs neurovascular restoration and worsens outcome in diabetes via the activation of TLR-4 by excess iron, a novel DAMP. To achieve our overall goals, Aim 1 will test the hypothesis that even petechial nonspace-occupying HT impairs neurovascular restorative repair and worsens neurological deficits in diabetes. Aim 2 will test the hypothesis that iron deposition resulting from greater HT in diabetes impairs neurovascular plasticity and worsens outcome of ischemic stroke. Aim 3 will test the hypothesis that HT stimulates TLR4 signaling and inflammation worsening repair and recovery after diabetic ischemic stroke. The data obtained from our translational studies will yield the following outcomes: a) we will challenge the existing paradigm that only space-occupying HT worsens outcomes and demonstrate that any bleeding into the brain is detrimental by impairing vascular and neuronal repair, b) we will generate new and important data related to mechanisms of how diabetes attenuates neuronal and endothelial repair processes by using various combinations of animal models of diabetes or stroke to recapitulate the clinical condition, and c) we will identify iron as a new DAMP and show that iron chelation and/or downstream TLR4 inhibition are promising therapeutic targets in stroke treatment/recovery. This project will significantly impact stroke research, human health and VA mission because it will 1) identify neurovascular protection & restoration strategies to improve stroke outcomes, 2) advance our knowledge of the role of the cerebral vasculature in stroke repair, and 3) provide specific information on stroke recovery in diabetes which occurs in more than 30% of the 800,000 annual stroke victims. We are well poised to take this challenge since we have established collaborations with VA scientists that have provided support for the goals of this proposal.