Modulating a critical inhibitory proteoglycan receptor to promote functional recovery after stroke

中风是全世界导致死亡和残疾的主要原因之一，给人们带来沉重的负担 在我们社会中的经济。目前中风的治疗策略主要集中在减少缺血的大小上 损害和在发生后早期拯救濒临死亡的细胞。治疗，如使用溶栓剂 药物，往往受到治疗时间窗口狭窄的限制。然而，大脑的再生在 中风发生几天甚至几周后，损伤仍然活跃，这可能提供第二个窗口 治疗。我们的初步数据表明，体内全身性传递阻断特定受体的多肽 硫酸蛋白多糖对卒中动物卒中后24小时和7天后胶质瘢痕的抑制作用 卒中后两者均能改善其功能恢复。我们假设CSPG信号通路参与了 卒中后神经再生和轴突萌发的调节及对CSPG的调节 在卒中康复中，信号通路将导致更好的功能结局。我们将在这两种情况下测试这一假设 幼龄和老年小鼠近端短暂性大脑中动脉闭塞(MCAO)动物模型。朝向 为了实现这一目标，我们制定了一项由三个具体目标组成的提案。在具体目标1和2中，我们将 研究CSPGs信号通路在年轻或老年中风动物功能恢复中的作用。在……里面 具体目标3，我们将结合遗传和神经修复研究中风动物的神经修复机制 可诱导细胞类型特异性σ基因敲除或isp多肽治疗的药理调节。二 将分析卒中神经修复的主要机制，包括神经发生和轴突萌发 基因和药物调节的中风动物。综上所述，对 中风动物的分子、细胞和行为测量将产生数据，这些数据将提供洞察力 论CSPG信号在神经损伤修复过程中的确切作用。获得的数据将是 直接适用于开发治疗脑缺血的新的治疗干预措施 中枢神经系统中细胞微环境的操纵。我们预计，这些资源和成果 将为神经再生研究开辟新的途径，并导致识别 分子治疗靶点。

Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Current treatment strategies for stroke primarily focus on reducing the size of ischemic damage and on rescuing dying cells early after occurrence. Treatments, such as the use of thrombolytic agents, are often limited by a narrow therapeutic time window. However, the regeneration of the brain after damage is still active days, or even weeks after stroke occurs, which might provide a second window for treatment. Our preliminary data suggests that systemic in vivo delivery of a peptide that blocks a specific receptor mediated inhibitory action of sulphated proteoglycans in the glial scar in stroke animals 24 hours after stroke or 7 days after stroke both improve their functional recovery. We hypothesize that the CSPG signaling pathway is involved in the regulation of neuroregeneration and axonal sprouting after stroke and that modulating the CSPG signaling pathway will lead to better functional outcome in stroke recovery. We will test this hypothesis in both young and aged mice in the proximal transient middle cerebral artery occlusion (MCAo) animal model. Towards this goal, we have developed a proposal that consists of three specific aims. In specific aim 1 and 2, we will investigate the role of the CSPGs signaling pathway in functional recovery in young or aged stroke animals. In specific aim 3, we will examine the mechanisms of neurorepair in stroke animals by combination of genetic and pharmacological modulation with inducible cell type specific RPTPσ knockout or ISP peptide treatment. Two main mechanisms of neurorepair including neurogenesis and axonal sprouting in stroke will be analyzed in genetically and pharmacologically modulated stroke animals. Together, the comprehensive analysis of molecular, cellular and behavioral measurements in stroke animals will generate data that will provide insights on the precise role of CSPG signaling in the process of injury-induced neurorepair. The data gained will be directly applicable to developing novel therapeutic interventions in treating cerebral ischemia through the manipulation of the cellular microenvironment in the CNS. We anticipate that the resources and results generated from our study will open new avenues in neuroregeneration research and lead to the identification of molecular therapeutic targets.