Mechanisms underlying Netrin-1-mediated functional recovery after stroke

描述（由申请人提供）： 中风仍然是美国长期残疾的主要原因。为促进脑卒中后的功能恢复，需要采取相应的康复策略。神经血管单元的概念和继发性损伤的多种机制正在改变我们治疗卒中的方法。局灶性脑缺血后，尽管梗死周围皮质的组织灌注以距离依赖性方式逐渐改善，但即使在数月后也从未完全恢复。很明显，局部血流动力学的恢复也影响了棘密度的恢复，并最终影响了突触可塑性。我们的初步研究结果表明，由AAV-Netrin-1基因治疗诱导的功能恢复与梗死周围皮质中血管密度的增加有关，这可能与netrin-1的促血管生成作用或预防继发性损伤有关。基于这些有希望的结果和netrin-1在抗炎和神经可塑性诱导中的不同作用，我们希望扩展我们的研究，以进一步研究netrin-1在脑缺血和功能恢复的背景下减少炎症和促进神经可塑性的治疗功效和潜在的信号传导机制。提出了以下具体目标：目标1。验证netrin-1基因转移通过腺苷2B受体减少卒中后慢性神经炎症的假设。为了区分血液与内皮A2 B受体的贡献，我们将使用骨髓移植来创建嵌合小鼠。目的2验证netrin-1基因转移通过netrin-1受体增强神经干细胞在缺血性梗死周围和白色物质中迁移的假设。目的3验证netrin-1基因转移增强苯丙胺的神经可塑性诱导作用和康复的假设。这里收集的概念验证数据可能会导致netrin-1作为中风治疗促进功能恢复的新靶点的发展。

DESCRIPTION (provided by applicant): Stroke remains the leading cause of long-term disability in the US. To enhance post stroke functional recovery, appropriate rehabilitation strategy is in dire need. The concept of neurovascular unit and the multiple mechanisms involved in secondary injury is changing our approach in stroke therapy. Following focal cerebral ischemia, although the tissue perfusion in the peri-infarct cortex improved gradually in a distance-dependent manner, it is never fully restored even months after. It is evident that the recovery of local hemodynamics also affected the recovery of spine density, and ultimately, synaptic plasticity. Our preliminary results establish that functional restoration induced by AAV-Netrin-1 gene therapy is associated with an increase in vascular density in the peri-infarct cortex, which could be related to netrin-1's proangiogenic effect or prevention of secondary injury. Based on these promising results and the diverse effects of netrin-1 in anti-inflammation and neuroplasticity induction, we would like to extend our study to further investigate the therapeutic efficacy of netrin-1 and underlying signaling mechanisms in reducing inflammation and promoting neuroplasticity in the context of brain ischemia and functional recovery. The following specific aims are proposed: Aim 1. Test the hypothesis that netrin-1 gene transfer reduces post stroke chronic neuroinflammation via adenosine 2B receptor. To distinguish the contribution of blood versus endothelial A2B receptors, we will use bone marrow transplants to create chimeric mice. Aim 2 will test the hypothesis that netrin-1 gene transfer enhances neural stem cell migration in the ischemic peri-infarct and white matter via specific netrin-1 receptors. Aim 3 will test the hypothesis that netrin-1 gene transfer augments the neuroplasticity inducing effect of amphetamine and rehabilitation. Proof-of-concept data collected here may lead to the development of netrin-1 as a novel target for stroke therapy in promoting functional recovery.