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

调节关键的抑制性蛋白聚糖受体以促进中风后的功能恢复

• 批准号: 10112316
• 负责人: Yu Luo
• 金额: $ 35.07万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112316
• 关键词: Acute; Animal Model; Animals; Area; Axon; Behavioral; Brain; Cause of Death; Cells; Cerebral Ischemia; Chondroitin Sulfates; Chronic Phase; Cicatrix; Clinical Treatment; Complement; Contralateral; Corpus striatum structure; Corticospinal Tracts; Data; Distal; Dose; Edema; Extracellular Matrix; Family; Fiber; Fibrinolytic Agents; Future; Genetic; Goals; Histologic; Hour; Human; Immunohistochemistry; Infarction; Inflammatory; Injections; Injury; Knock-out; Knockout Mice; Label; Lead; Lesion; Mammals; Measures; Mediating; Middle Cerebral Artery Occlusion; Molecular; Molecular Analysis; Mus; Natural regeneration; Nerve Regeneration; Neural Inhibition; Neuroglia; Neurons; Pathway interactions; Peptides; Pharmacology; Play; Process; Proteoglycan; Recovery; Recovery of Function; Regulation; Research; Resources; Role; Route; Series; Signal Pathway; Signal Transduction; Societies; Solid; Stroke; Survival Rate; Synapsins; Techniques; Testing; Therapeutic; Time; Tissues; Traumatic CNS injury; Treatment outcome; aged; axon regeneration; axonal sprouting; base; behavior measurement; cell motility; cell type; comparative efficacy; conditional knockout; disability; efficacy evaluation; efficacy testing; experimental study; functional outcomes; improved; in vivo; insight; juvenile animal; migration; molecular targeted therapies; mouse model; nestin protein; neuroblast; neurogenesis; novel; novel therapeutic intervention; post stroke; precursor cell; programs; receptor; regenerative; repaired; response; stem cell migration; stem cells; stroke model; stroke recovery; stroke therapy; treatment strategy

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.

中风是全球死亡和残疾的主要原因之一，对 我们社会的经济。当前的中风的治疗策略主要关注减少缺血大小 损坏并在发生后尽早营救垂死的细胞。治疗，例如使用溶栓 代理通常受到狭窄的治疗时间窗口的限制。但是，大脑的再生之后 伤害仍然是活跃的日子，甚至是中风后几周，这可能会提供第二个窗口 治疗。我们的初步数据表明，全身性体内递送肽阻断了特定的接收器 中风动物的胶质疤痕中硫化蛋白聚糖的抑制作用24小时或7天 中风后都可以改善其功能恢复。我们假设CSPG信号通路涉及 在调节中风后神经变成和轴突发芽中，调节CSPG 信号通路将导致中风恢复中更好的功能结果。我们将在两者中检验这一假设 近端瞬时脑动脉闭塞（MCAO）动物模型中的年轻小鼠和老年小鼠。向 这个目标，我们制定了一个由三个特定目标组成的建议。在特定的目标1和2中，我们将 研究CSPGS信号通路在年轻或老年人动物功能恢复中的作用。在 特定目标3，我们将通过遗传和遗传和 具有诱导细胞类型的特异性RPTPσ基因敲除或ISP胡椒处理的药理调节。二 神经膜的主要机制将在中风中进行神经发生和轴突发芽。 遗传和身体调制的中风动物。一起，对 中风动物中的分子，细胞和行为测量将产生可提供见解的数据 关于CSPG信号在损伤引起的神经卫星过程中的确切作用。获得的数据将是 直接适用于开发新的热干预措施，以通过 CNS中细胞微环境的操纵。我们预计资源和结果 我们的研究产生的将开放神经创造研究的新途径，并导致鉴定 分子治疗靶标。