Vascular Injury and Recovery in Diabetic Ischemic Stroke

描述(申请人提供)：超过7%的患有糖尿病的美国人患缺血性中风的风险是前者的2到6倍，并遭受不良的中风结局和糟糕的康复。组织纤溶酶原激活剂(TPA)再灌注治疗是治疗缺血性卒中的唯一方法；然而，这种治疗增加了出血进入大脑(出血性转化，HT)的风险，尤其是在糖尿病患者中。在开发新的治疗策略以及在高危人群中正确使用tPA方面取得进展的一个关键障碍是缺乏对出血如何影响中风后修复和恢复的了解。我们的目标是确定预防和治疗既有血管疾病的I型中风患者的新靶点，并开发新的神经血管保护策略。我们的目标是通过明确高血压对糖尿病缺血性卒中后神经血管修复的影响和机制来解决这一关键障碍和临床问题。我们的中心假设是，出血进入大脑，点状或占位，通过过量铁激活Toll样受体(TLR)-4，一种新的损伤相关分子模式(DAMP)，损害了神经血管的恢复，并恶化了糖尿病的预后。这一假说将在3个特定的目标进行检验：1.检验斑点非占位性高压病损害神经血管恢复性修复和加重糖尿病神经功能障碍的假说。我们将确定在多种中风和糖尿病模型中，高血压对神经血管修复和功能结果的损害程度；2.检验糖尿病中较大的高血压导致铁沉积损害神经血管可塑性和恶化缺血性中风预后的假说。我们将确定铁在2型糖尿病栓塞性卒中后神经血管恢复和功能结局中的作用；以及3.验证羟色胺刺激TLR4信号/炎症恶化糖尿病缺血性卒中后修复和恢复的假说。我们将确定高血压损害2型糖尿病栓塞性卒中后功能恢复的机制。我们的翻译研究成果包括：1)证明任何进入大脑的出血都会损害血管和神经元的修复(这挑战了只有占据空间的羟色胺才会恶化预后的现有范式)；2)通过使用多种糖尿病或中风的动物模型来总结临床情况，产生了与糖尿病如何减弱神经元和内皮修复过程的机制相关的新的重要数据；3)确认铁是一种新的湿气，并表明铁螯合和/或下游抑制TLR4是中风治疗/康复的有希望的治疗靶点。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)确定改善中风预后的神经血管保护和恢复策略，2)增进我们对脑血管在中风修复中作用的了解，3)提供糖尿病中风康复的具体信息，每年80万中风患者中有30%以上的人患有糖尿病。

DESCRIPTION (provided by applicant): 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 i 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 space- occupying, 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 and 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.