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，他们的糖尿病发病率不仅是 患急性缺血性中风的风险较高，但也患有不良的中风结局和不良 恢复。组织纤溶酶原激活物(TPA)再灌注治疗是缺血性卒中的唯一治疗方法； 然而，这种治疗增加了脑出血(出血性转化，HT)的风险 糖尿病患者。在开发新的治疗策略方面取得进展的关键障碍是这种高风险 人群缺乏对出血严重程度如何影响糖尿病患者卒中结局和康复的了解。 此续订申请的具体目标是通过定义影响来解决这一关键障碍 以及糖尿病患者缺血性中风后羟色胺损害神经血管修复的机制。在过去 资助期我们报道：a)2型患者有健壮的病理性新生血管。 糖尿病，b)再灌注损伤叠加在这种病理上会放大羟色胺并恶化神经功能。 缺血量不增加梗塞面积，以及c)在没有再灌流的情况下，没有羟色胺，也没有差别 在对照组和糖尿病动物之间的功能结果。这些新的结果引导我们识别大脑 血管系统和羟色胺作为糖尿病缺血性卒中的治疗靶点。危险相关的分子模式 (DAMPS)，细胞死亡时释放的细胞内分子，是一个新兴的概念，参与了 通过Toll样受体(TLRs)激活天然免疫系统。在此基础上，中央 假说是，出血进入大脑，点状或占位性，会损害神经血管的恢复 并通过过量铁激活TLR-4而恶化糖尿病的结局，这是一种新的湿气。为了实现我们的目标 总体目标，目标1将检验假设，即使是点状非占位的HT也会损害 神经血管恢复性修复和加重糖尿病患者的神经功能缺陷。目标2将检验这一假设 糖尿病患者由于高血压引起的铁沉积损害了神经血管的可塑性，恶化了 缺血性卒中的结局。目标3将检验这一假设，即羟色胺刺激TLR4信号和 炎症加重糖尿病缺血性卒中后的修复和恢复。从我们的网站获得的数据 翻译研究将产生以下结果：a)我们将挑战现有的范式，只有 占据空间的HT会恶化预后，并证明任何进入大脑的出血都是有害的，因为 损伤血管和神经元修复，b)我们将产生与以下机制相关的新的重要数据 糖尿病如何通过使用不同的动物组合来减弱神经元和内皮修复过程 糖尿病或中风的模型，以概括临床情况，以及c)我们将确定铁是一种新的湿气 表明铁络合和/或抑制TLR4下游是治疗中风的有希望的靶点 治疗/康复。该项目将对中风研究、人类健康和退伍军人管理局任务产生重大影响 因为它将1)确定神经血管保护和恢复策略，以改善中风结果，2) 促进我们对脑血管在中风修复中的作用的了解，以及3)提供特定的 每年80万中风患者中30%以上发生的糖尿病患者的中风康复信息 受害者。我们已经做好准备迎接这一挑战，因为我们已经与退伍军人管理局的科学家建立了合作关系 它们为这项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.