Vascular Injury and Recovery in Diabetic Ischemic Stroke

超过7%的美国糖尿病患者患缺血性心脏病的风险是普通人的2到6倍 中风，并遭受不良的中风结局和恢复不良。组织再灌注疗法 纤溶酶原激活剂(TPA)是治疗缺血性卒中的唯一方法；然而，这种治疗增加了风险 出血进入大脑(出血性转化，HT)，尤其是糖尿病患者。一个严重的障碍 开发新的治疗策略的进展以及tPA在高危疾病中的正确使用 人们对出血如何影响中风后的修复和恢复缺乏了解。我们的 目标是确定预防和治疗既有血管患者卒中的新靶点 并开发新的神经血管保护策略。我们的目标是解决这一关键障碍 和临床问题，通过定义高血压损害神经血管修复的影响和机制 糖尿病合并缺血性中风。我们的中心假设是出血进入大脑，点状或占位， 通过激活Toll样蛋白损害神经血管的恢复并恶化糖尿病的预后 受体(TLR)-4通过过量铁，一种新的损伤相关的分子模式(DAMP)。这一假说将 测试3个具体目标：1.测试斑点非占位性羟色胺损伤的假说 神经血管恢复性修复和加重糖尿病患者的神经功能缺陷。我们将确定在多大程度上 结论：1.高血压损害了多种中风和糖尿病模型的神经血管修复和功能结局； 检验糖尿病患者高血压引起的铁沉积损害神经血管可塑性的假说 并加重缺血性卒中的预后。我们将确定铁在神经血管修复和修复中的作用 2型糖尿病栓塞性卒中后的功能结局；3.检验羟色胺刺激的假说 TLR4信号/炎症加重糖尿病缺血性卒中后的修复和恢复。我们将决定 高血压损害2型糖尿病栓塞性卒中后功能恢复的机制这个 我们的翻译研究结果包括：1)证明任何进入大脑的出血都是有害的 通过损害血管和神经元修复(这挑战了仅占据空间的现有范式 高血压恶化预后)；2)产生与糖尿病机制有关的新的重要数据 通过使用糖尿病或糖尿病动物模型的组合来减弱神经元和内皮修复过程 总结中风病的临床情况，3)辨证铁质为新湿，说明铁质 螯合和/或下游抑制TLR4是卒中治疗/康复的有前途的治疗靶点。 该项目将对中风研究和人类健康产生重大积极影响，因为它将1) 确定神经血管保护和恢复策略以改善中风预后，2)促进我们的 了解脑血管在中风修复中的作用，以及3)提供有关中风的具体信息 糖尿病的康复，每年80万中风患者中有30%以上的人患有糖尿病。

More than 7% of the US population who have diabetes are at a 2 to 6-fold higher risk for having ischemic stroke and 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), especially in diabetics. A critical barrier to progress in the development of new therapeutic strategies, as well as the proper use of tPA in high-risk populations, is the lack of understanding on how bleeding influences the repair and recovery after stroke. Our goal is to identify new targets for prevention and treatment of stroke in patients with preexisting vascular disease and develop new neurovascular protection strategies. Our objective is to address this critical barrier and clinical problem by defining the impact and mechanisms by which HT impairs neurovascular repair after ischemic stroke in diabetes. Our central hypothesis is that bleeding into the brain, petechial OR spaceoccupying, impairs neurovascular restoration and worsens outcome in diabetes via the activation of toll like receptor (TLR)-4 by excess iron, a novel damage associated molecular pattern (DAMP). This hypothesis will be tested in 3 Specific Aims: 1. Test the hypothesis that petechial nonspace-occupying HT impairs neurovascular restorative repair and worsens neurological deficits in diabetes. We will determine the extent to which HT impairs neurovascular repair and functional outcome in multiple models of stroke and diabetes; 2. Test the hypothesis that iron deposition resulting from greater HT in diabetes impairs neurovascular plasticity and worsens outcome of ischemic stroke. We will determine the role of iron on neurovascular restoration and functional outcome after embolic stroke in Type 2 diabetes; and 3. Test the hypothesis that HT stimulates TLR4 signaling/inflammation worsening repair and recovery after diabetic ischemic stroke. We will determine the mechanisms by which HT impairs functional recovery after embolic stroke in Type 2 diabetes. The outcomes of our translational studies include: 1) demonstrating that any bleeding into the brain is detrimental by impairing vascular and neuronal repair (this challenges the existing paradigm that only space-occupying HT worsens outcomes); 2) generating new and important data related to mechanisms of how diabetes attenuates neuronal and endothelial repair processes by using combinations of animal models of diabetes or stroke to recapitulate the clinical condition, and 3) identification of 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 have a significant positive impact on stroke research and human health 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.