Brain neovascularization in diabetes

描述(由申请人提供)：急性缺血性中风是美国残疾的主要原因。通过刺激大脑的恢复机制来改善功能结果的治疗策略对每年超过70万中风患者大有可为。由于脑功能在很大程度上依赖于脑血流，因此在中风的实验模型中，使用促血管生成剂和/或干细胞促进血管生成被评估为一种治疗方式。虽然2型糖尿病存在于近40%的急性缺血性卒中患者中，并使卒中预后恶化，但糖尿病如何影响脑血管生成和神经血管单位结构，从而总体上影响脑损伤和康复的病理生理和程度尚不清楚。这一探索性的R21应用的目的是了解2型糖尿病对中风前后脑血管新生和神经血管模式的影响。我们发现，糖尿病刺激脑血管重塑/动脉生成，缺血性脑损伤叠加在这种病理上导致较小的脑梗塞，但更大的出血转化(HT)和较差的功能结果。我们最近在非糖尿病大鼠身上的令人兴奋的数据表明，缺血性卒中后的血管生成反应依赖于氧化还原信号的优化。基于这些发现，中心假设是糖尿病以氧化还原依赖的方式不同地调节中风前后的脑血管生成。我们将在两个特定的目标上验证这一假说：目的1：确定糖尿病和糖尿病卒中对脑血管生成的影响，目的2：确定缺血/再灌注产生的氧化应激在糖尿病血管生成血管内皮生长因子(VEGF)信号转导中的作用。加强对糖尿病背景下脑血管网络的了解，不仅可以为高危患者制定卒中预防和治疗策略，还可以改善卒中的治疗性血管生成。鉴于每年70万名缺血性中风患者中有超过40%的患者有糖尿病病史，我们相信这个项目具有转化性，将对人类健康产生重大的积极影响。 公共卫生相关性：绝大多数中风患者患有糖尿病。这些患者有严重的中风后果。该项目将确定糖尿病条件下中风前和中风后的血管保护机制，以制定这些高危患者的治疗策略。

DESCRIPTION (provided by applicant): Acute ischemic stroke is the leading cause of disability in the United States. Therapeutic strategies to improve functional outcome by stimulating brain's recovery mechanisms hold a great promise for more than 700,000 annual stroke victims. Since brain function is heavily dependent on cerebral blood flow, enhancement of angiogenesis by proangiogenic agents and/or stem cells is being evaluated as a therapeutic modality in experimental models of stroke. Although type 2 diabetes is present in almost 40% of the acute ischemic stroke patients and worsens stroke outcome, how diabetes affects cerebral angiogenesis and neurovascular unit architecture that overall may influence the pathophysiology and magnitude of brain injury and recovery is not known. The objective of this exploratory R21 application is to understand the impact of type 2 diabetes on brain neovascularization and neurovascular patterning before and after stroke. We showed that diabetes stimulates cerebrovascular remodeling/arteriogenesis and ischemic brain injury superimposed on this pathology results in smaller infarcts but greater hemorrhagic transformation (HT) and poor functional outcomes. Our recent exciting data in nondiabetic rats suggested that angiogenic response after ischemic stroke depends on the optimization of redox signaling. Based on these findings, the central hypothesis is that diabetes differentially regulates cerebral angiogenesis before and after stroke in a redox-dependent manner. We will test this hypothesis in 2 specific aims: Aim 1: Determine the effect of diabetes and diabetic stroke on cerebral angiogenesis, and Aim 2: Determine the role of ischemia/reperfusion-generated oxidative stress on angiogenic vascular endothelial growth factor (VEGF) signaling in diabetes. An enhanced understanding of cerebrovascular networking in the setting of diabetes would not only allow us to develop preventive and therapeutic strategies for stroke in high risk patients but also improve therapeutic angiogenesis in stroke. Given that more than 40% of 700,000 annual ischemic stroke patients have a history of diabetes, we believe this project is translational in nature and will have a significant positive impact on human health. PUBLIC HEALTH RELEVANCE: A great majority of stoke patients have diabetes. These patients have severe stroke outcomes. This project will determine the mechanisms of vascular protection before and after stroke under diabetic conditions to develop treatment strategies in these high risk patients.