Vascular Injury and Recovery in Diabetic Ischemic Stroke

描述（由申请人提供）：超过7%的美国糖尿病患者发生缺血性卒中的风险高出2至6倍，卒中预后不良且恢复不良。组织型纤溶酶原激活剂（tPA）再灌注治疗是缺血性脑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，特别是在糖尿病患者中。在开发新的治疗策略以及在高危人群中正确使用tPA方面，一个关键的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卒中患者既往存在血管疾病的新靶点，并制定新的神经血管保护策略。我们的目标是通过确定HT损害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，过量铁激活toll样受体(TLR)-4（一种新的损伤相关分子模式（DAMP）），导致脑出血、点状或占位损害神经血管修复，并恶化糖尿病的预后。这一假设将在三个具体目标中进行检验：1。验证点状非占位性HT损害糖尿病患者神经血管恢复性修复并加重神经功能缺损的假设。我们将在多种中风和糖尿病模型中确定HT损害神经血管修复和功能结局的程度；2. 验证糖尿病患者HT升高导致的铁沉积损害神经血管可塑性并恶化缺血性卒中预后的假设。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；和3。验证HT刺激TLR4信号/炎症恶化糖尿病缺血性脑卒中后修复和恢复的假设。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。我们的转化研究结果包括：1)证明任何进入大脑的出血都是有害的，因为它损害了血管和神经元的修复（这挑战了现有的范式，即只有占用空间的HT会使结果恶化）；2)通过结合糖尿病或脑卒中动物模型来总结临床情况，为糖尿病如何减弱神经元和内皮细胞修复过程的机制提供新的重要数据；3)确定铁作为一种新的DAMP，并表明铁螯合和/或下游TLR4抑制是脑卒中治疗/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，以改善中风结果，2)推进我们对脑血管系统在中风修复中的作用的认识，以及3)提供糖尿病中风恢复的具体信息，糖尿病在每年80万中风患者中占30%以上。

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.