COLLATERAL FORMATION AND REMODELING AFTER ISCHEMIC STROKE

项目摘要/摘要 中枢神经系统(CNS)的脑血管疾病仍然是发病率的主要原因 以及美国的死亡率。血管闭塞后的缺血性损伤通常由血管闭塞的程度决定。 血管内皮细胞的丢失以及随后对先前存在的侧支血管的修复和重建。一种方法是 最大限度地减少神经损伤的程度是鼓励侧支生成作为恢复血液流动的一种手段 脆弱的邻近组织。广泛的血管网络已被证明支持侧支循环。 并减轻由此导致的神经血管缺陷；然而，调节自然形成和 损伤诱导侧支血管网络的重建在很大程度上是未知的。 目前的提案 概述了原则证明实验，这些实验将促进我们对 EPhin/Eph信号转导 可能 最近，EphA4受体功能丧失的研究表明 软脑膜表面小动脉侧支血管形成。这些和其他初步数据是第一批 基因消融后大脑皮层侧支血管数量增加。基座 在之前和初步的实验中，我们建议检验EphA4受体是 缺血性卒中后大脑皮层上调，负向调节侧支生成，从而限制 恢复血流量和组织保存。在目标1中，我们将研究EphA4在 NA、Sham和缺血损伤大鼠大脑皮质软膜表面小动脉和内皮相关星形胶质细胞 老鼠。在目标2中，我们将评估细胞特异性EphA4缺失对内皮细胞和/或星形胶质细胞的影响 卒中后侧支循环、闭塞后血流和脑梗塞体积。最后，我们将确定是否 商业上可获得的EphA4阻滞剂的治疗性交付也可以促进侧支循环和 阻碍侧支循环的进程。 目标3中的修复。总的来说，这些研究将评估 EphA4在体表侧支发生中的作用 这次调查还将增加一些 在基础和翻译血管研究方面取得了令人兴奋的进展。因此，拟议的研究与以下方面有关 美国国立卫生研究院的使命是促进创新的研究战略，以提高国家改善 健康和让研究实习生在生物医学实验室环境中亲身体验。 使用转基因小鼠和药物传递方法的软脑膜小动脉。

Project Summary/Abstract Cerebrovascular disease of the central nervous system (CNS) remains a leading cause of morbidity and mortality in the US. Ischemic injury following vascular occlusion is often dictated by the extent of endothelial cell loss and subsequent repair and remodeling of pre-existing collateral vessels. One approach to minimizing the extent of neural damage is to encourage collaterogenesis as a means of restoring blood flow to the vulnerable adjacent tissue. An extensive vascular network has been shown to support collateral blood flow and mitigate the resulting neurovascular defects; however, the mechanism(s) regulating native formation and injury-induced re-establishment of the collateral vascular network are largely unknown. The current proposal outlines proof-of-principle experiments that will advance our understanding of how ephrin/Eph signaling may Recently, EphA4 receptor loss-of-function studies demonstrate robust surface pial arteriole collateral vessel formation. These and other preliminary data are one of the first demonstrations of increased collateral vessel numbers in the cerebral cortex following gene ablation. Based on previous and preliminary experiments, we propose to test the hypothesis that EphA4 receptor is upregulated in the cortex after ischemic stroke and negatively regulates collaterogenesis, thereby limiting restoration of blood flow and tissue preservation. In Aim 1 we will examine the expression pattern of EphA4 on surface pial arterioles and endothelial associated astrocytes in the cortex of na¿ve, sham and ischemic-injured mice. In Aim 2 we will evaluate how cell-specific EphA4 deletion on endothelial cells and/or astrocytes effects collaterogenesis, post-occlusion blood flow and infarct volume after stroke. Finally, we will determine whether therapeutic delivery of commercially available blockers of EphA4 also can promote collateral blood flow and impede the process of collaterogenesis. repair in Aim 3. Overall, these studies will assess t he functional role of EphA4 on collaterogenesis of surface This investigation will also add some exciting progress in basic and translational vascular research. Thus, the proposed research is relevant to the NIH's mission to foster innovative research strategies to advance the nation's capacity to improve health and expose research trainees to hands on experience in a biomedical laboratory setting. pial arterioles using both transgenic mice and drug delivery approaches.