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其他人群的2至6倍。 中风且遭受不利中风结果和不良恢复。组织再灌注治疗 纤溶酶原激活剂（tPA）是缺血性卒中的唯一治疗方法;然而，这种治疗增加了 出血性转化（hemorrhagic transformation，HT），尤其是糖尿病患者。一个关键的障碍， 在开发新的治疗策略方面取得的进展，以及在高风险患者中正确使用tPA 然而，在大多数人群中，缺乏对出血如何影响中风后修复和恢复的理解。我们 目的是确定预防和治疗已有血管病变患者卒中的新靶点， 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 通过定义HT损害神经血管修复的影响和机制， 糖尿病缺血性中风我们的中心假设是脑出血，瘀点或占位， 通过激活Toll样蛋白损害神经血管恢复和糖尿病的预后 受体（TLR）-4过量铁，一种新的损伤相关分子模式（DAMP）。这一假设将 在3个具体目标进行测试：1。检验瘀点非占位性HT损害 神经血管恢复性修复和糖尿病的神经功能缺损。我们将确定 其中HT在多种中风和糖尿病模型中损害神经血管修复和功能结果; 2. 验证糖尿病患者HT增加导致铁沉积损害神经血管可塑性的假设 和缺血性卒中的预后。我们将确定铁在神经血管恢复中的作用， 2型糖尿病栓塞性卒中后的功能结局;和3.测试HT刺激 糖尿病缺血性卒中后TLR 4信号转导/炎症恶化修复和恢复。我们将确定 HT损害2型糖尿病栓塞性卒中后功能恢复的机制。的 我们的转化研究的结果包括：1）证明任何出血进入大脑是有害的， 通过损害血管和神经元修复（这挑战了现有的范式， HT的结果）; 2）产生新的和重要的数据，与糖尿病如何 通过使用糖尿病动物模型的组合减弱神经元和内皮修复过程，或 3）铁作为一种新的DAMP被鉴定，并表明铁 螯合和/或下游TLR 4抑制是中风治疗/恢复中有希望的治疗靶点。 该项目将对中风研究和人类健康产生重大的积极影响，因为它将1） 确定神经血管保护和恢复策略，以改善卒中结局，2）推进我们的 了解脑血管系统在卒中修复中的作用，以及3）提供卒中的具体信息 在每年80万中风患者中，超过30%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.