Brain neovascularization in diabetes

糖尿病脑新生血管形成

• 批准号: 8072967
• 负责人: ADVIYE ERGUL
• 金额: $ 22.35万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072967
• 关键词: Acute; Affect; Apoptosis; Architecture; Blood Vessels; Brain; Brain Injuries; Cerebrovascular Circulation; Cerebrum; Data; Diabetes Mellitus; Diabetic Retinopathy; Disease; Equilibrium; Experimental Models; Figs - dietary; Functional disorder; Goals; Health; Human; Hypoxia; In Vitro; Infarction; Injury; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Measures; Middle Cerebral Artery Occlusion; Modality; Nature; Nervous System Physiology; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Oxidative Stress; Pathologic Neovascularization; Pathology; Patients; Pattern; Peroxonitrite; Prevention; Preventive; Property; Rattus; Recording of previous events; Recovery; Recovery of Function; Reperfusion Injury; Reperfusion Therapy; Role; Signal Transduction; Stem cells; Stroke; Structure; Testing; Therapeutic; Tube; United States; Vascular Endothelial Growth Factors; Work; angiogenesis; base; cerebrovascular; density; diabetic; diabetic rat; disability; functional outcomes; high risk; improved; migration; neovascularization; neurovascular unit; nitration; non-diabetic; response; therapeutic angiogenesis; three dimensional structure; treatment strategy

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.

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超过70万名年度中风受害者有着巨大的希望。由于大脑功能在很大程度上取决于脑血流，因此在实验模型的实验模型中，正在评估促血管生成剂和/或干细胞对血管生成的增强。尽管几乎40％的急性缺血性中风患者中存在2型糖尿病，并且中风的结果恶化，但尚不知道糖尿病如何影响大脑血管生成和神经血管单位结构，总体上可能会影响脑损伤的病理生理学和大小的脑损伤和康复。此探索性R21应用的目的是了解2型糖尿病对中风前后的脑新血管形成和神经血管模式的影响。我们表明，糖尿病刺激脑血管重塑/动脉生成和缺血性脑损伤叠加在这种病理学上会导致梗塞较小，但出血性转化（HT）较大，功能性不佳。我们最近在非糖尿病大鼠中的令人兴奋的数据表明，缺血性中风后的血管生成反应取决于氧化还原信号传导的优化。基于这些发现，中心假设是糖尿病以氧化还原依赖性方式差异化调节脑血管生成。我们将在两个特定目的中检验这一假设：目标1：确定糖尿病和糖尿病性中风对脑血管生成的影响，目标2：确定缺血/再灌注产生的氧化应激对糖尿病中血管生成血管生长生长因子（VEGFF）信号的作用。在糖尿病的情况下，对脑血管网络的了解增强了，不仅使我们能够在高风险患者中开发预防和治疗性的中风策略，而且可以改善中风中的治疗性血管生成。鉴于，在700,000个年度缺血性中风患者中，有40％以上有糖尿病病史，我们认为该项目本质上是转化的，将对人类健康产生重大积极影响。 公共卫生相关性：大多数Stoke患者患有糖尿病。这些患者的中风结果严重。该项目将确定在糖尿病状况下中风前后血管保护的机制，以制定这些高风险患者的治疗策略。