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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.

中风是世界范围内导致死亡和残疾的主要原因之一，给社会带来沉重负担