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

基本信息

批准号：
10380110
负责人：
Yu Luo
金额：
$ 35.15万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380110
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 neural repair neuroblast neurogenesis novel novel therapeutic intervention post stroke precursor cell programs receptor regenerative response stem cell migration stem cells stroke model stroke recovery stroke therapy treatment strategy

项目摘要

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.

中风是全世界死亡和残疾的主要原因之一，给人们带来沉重负担当前中风的治疗策略主要集中在减少缺血性病变的范围。损害以及在发生后尽早挽救垂死的细胞。然而，药物治疗后的大脑再生往往受到狭窄的治疗时间窗口的限制。中风发生后数天甚至数周，损伤仍然活跃，这可能提供第二个窗口期我们的初步数据表明，系统性体内递送肽可阻断特定受体。中风后 24 小时或 7 天，硫酸化蛋白多糖在中风动物神经胶质疤痕中介导的抑制作用我们发现 CSPG 信号通路参与了中风后的功能恢复。中风后神经再生和轴突萌芽的调节以及 CSPG 的调节信号通路将在中风恢复中带来更好的功能结果，我们将在这两种情况下检验这一假设。近端短暂大脑中动脉闭塞（MCAo）动物模型中的年轻和老年小鼠。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 CSPG 信号通路在年轻或老年中风动物功能恢复中的作用。具体目标3，我们将通过结合遗传和中风动物的神经修复机制来研究中风动物的神经修复机制。通过诱导细胞类型特异性 RPTPσ 敲除或 ISP 肽治疗进行药理调节两种。神经修复的主要机制，包括中风中的神经发生和轴突萌芽，将在以下章节中进行分析遗传和药理调节中风动物的综合分析。中风动物的分子、细胞和行为测量将生成可提供见解的数据所获得的数据将是关于 CSPG 信号在损伤诱导的神经修复过程中的精确作用。直接适用于开发治疗脑缺血的新型治疗干预措施我们预计中枢神经系统细胞微环境的资源和结果。我们的研究产生的结果将为神经再生研究开辟新途径，并导致识别分子治疗靶点。