Molecular Therapies to Promote White Matter Restoration After Traumatic Brain Injury

分子疗法促进脑外伤后白质恢复

基本信息

批准号：
9017340
负责人：
MICHAEL V L BENNETT
金额：
$ 40.62万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9017340
关键词：
Action Potentials Acute Alteplase Amino Acid Substitution Amino Acids Anti-Inflammatory Agents Anti-inflammatory Antioxidants Axon Behavioral Binding Blood - brain barrier anatomy Brain Brain Edema Cause of Death Cell Differentiation process Cerebral hemisphere hemorrhage Clinic Clinical Coculture Techniques Cognitive deficits Data Demyelinations Dose Electrophysiology (science)Epidermal Growth Factor Receptor Exhibits FDA approved Failure Fiber Fostering Generations Genes Human Injury Intervention Intranasal Administration Ischemic Stroke Knock-out Knockout Mice Mediating Membrane Modeling Molecular Mus Myelin Myelin Sheath Nervous System Physiology Neuraxis Neurites Neurological outcome Neurons Nuclear Receptors Oligodendroglia Outcome Peptide Hydrolases Peroxisome Proliferator-Activated Receptors Plasminogen Activator Play Prevention therapy Process Proliferating Recovery Recovery of Function Reporting Research Risk Role Serine Protease Signal Transduction Staging System Testing Therapeutic Agents Time Traumatic Brain Injury Traumatic Brain Injury recovery axon regeneration axonal degeneration axonal sprouting base controlled cortical impact deprivation disability functional improvement gray matter improved in vivo injured mouse model mutant myelination neglect neurological recovery neurorestoration novel oligodendrocyte precursor overexpression pre-clinical precursor cell public health relevance receptor remyelination repaired restoration thrombolysis white matter white matter injury young adult

项目摘要

DESCRIPTION (provided by applicant): White matter (WM) injury, which is characterized by axonal degeneration and loss of the myelin sheath (demyelination), is important for the long-term functional deficits after traumatic brain injury (TBI). The central nervous system exhibits limited capacity for WM repair, such as axonal regeneration and remyelination. During post-TBI WM repair, oligodendrocyte precursor cells (OPCs) are known to actively proliferate. However, many newly generated OPCs fail to differentiate into mature, myelin- This application will examine the effect of intranasal delivery of protease inactive plasminogen activator mutant (tPAm) to enhance differentiation and maturation of oligodendyocytes to promote white matter integrity following TBI. producing oligodendrocytes (OLs), resulting in inadequate remyelination. Failed remyelination not only diminishes signal transduction, but also leads to axon degeneration and worsens clinical outcome. Thus, interventions that promote OPC differentiation and maturation are promising strategies to enhance WM repair and improve functional recovery. Recombinant tissue plasminogen activator (tPA) is an FDA-approved treatment for ischemic stroke and catalyzes thrombolysis through serine protease action. Recent studies have discovered direct neurorestorative effects of tPA independent of protease activities. However, the clinical use of tPA as a therapeutic agent in TBI raises several concerns, as it can also cause blood-brain barrier damage and brain edema. In this proposal, we will explore protease-inactive mutant tPA (tPAm), with substitution of a single amino acid (S478A) to eliminate protease action, as a novel restorative therapy to promote remyelination and WM repair after TBI. We discovered that nanomolar concentrations of tPAm promote the differentiation of cultured primary OPCs into mature OLs. In addition, tPA knockout exacerbates behavioral deficits and WM injury lasting at least 35 days after TBI whereas post-injury intranasal administration of tPAm improves long-term neurological function and WM integrity after TBI in mice. Pilot data further suggest that tPAm enhances WM repair after TBI by promoting OPC differentiation and axon remyelination and that the effect may be mediated by the peroxisome proliferator-activated receptor γ (PPARγ) nuclear receptor. Here we will focus on the novel remyelinating actions of tPAm and test the following hypothesis: Treatment with protease inactive tPAm facilitates WM repair and long-term neurological recovery after TBI, at least in part, by inducing OPC differentiation and axonal myelination through PPARγ activation. Three Specific Aims will be tested. Aim 1: Determine whether post-TBI treatment with tPAm enhances WM integrity and promotes long-term recovery. Aim 2: Test the hypothesis that tPAm induces OPC differentiation/maturation and promotes axonal myelination through PPAR activation. Aim 3: Test the hypothesis that tPAm-induced OPC differentiation and axonal myelination are essential for the protection of WM integrity and long-term recovery after TBI. These studies are the first to investigate the potential for tPAm to foster remyelination in TBI an will identify the underlying mechanism of action, thereby setting the stage for the potential use o tPAm in the clinic.

描述（由应用提供）：白质（WM）损伤的特征是轴突变性和髓鞘鞘的丢失（脱髓鞘）对于创伤性脑损伤后的长期功能缺乏（TBI）很重要。中枢神经系统表现出有限的WM修复能力，例如轴突再生和再生。在TBI WM修复过程中，已知少突胶质细胞前体细胞（OPC）积极增殖。然而，许多新生成的OPC无法分化为成熟的OPC，髓磷脂将检查蛋白酶无活性纤溶酶原激活剂突变体（TPAM）的鼻内递送的作用，以增强少突胶质细胞的分化和成熟，以促进TBI之后的白质学整合性。产生少突胶质细胞（OLS），导致透明度不足。失败的延期不仅减少信号转导，还导致轴突变性并恶化临床结果。这是促进OPC分化和成熟的干预措施是增强WM修复并改善功能恢复的有前途的策略。重组组织纤溶酶原激活剂（TPA）是通过FDA批准的缺血性中风的治疗方法，并通过丝氨酸蛋白酶作用催化了稳态。最近的研究发现了独立于蛋白酶活性的TPA的直接神经理化作用。但是，在TBI中，TPA作为治疗剂的临床使用引起了一些关注，因为它也可能导致血脑屏障损伤和脑水肿。在此提案中，我们将探索蛋白质不活跃的突变体TPA（TPAM），并取代单个氨基酸（S478A）来消除蛋白酶的作用，作为一种新型的恢复性疗法，以促进TBI后促进Remereliation和WM修复。我们发现TPAM的纳摩尔浓度促进了培养的原代OPC分化为成熟的OL。此外，TPA敲除加剧了行为，定义了TBI后至少35天持续35天的WM损伤，而TPAM的伤害后给药可改善小鼠TBI后TBI的长期神经功能和WM完整性。飞行员数据进一步表明，TPAM通过促进OPC分化和轴突再效率增强了TBI后的WM修复，并且该作用可能是由过氧化物组增殖物激活的受体γ（PPARγ）核接收器介导的。在这里，我们将重点关注TPAM的新型透明作用，并检验以下假设：蛋白酶无效的TPAM TPAM设施WM修复和TBI后的长期神经系统恢复至少部分通过PPARγ激活诱导的OPC分化和轴突性髓鞘化。将测试三个具体目标。 AIM 1：确定TPAM治疗后TBI治疗是否可以增强WM完整性并促进长期恢复。 AIM 2：测试TPAM诱导的OPC分化/成熟并通过PPAR激活促进轴突髓鞘的假设。 AIM 3：检验TPAM诱导的OPC分化和轴突髓鞘化的假设对于保护WM完整性和TBI后的长期恢复至关重要。这些研究是第一个研究TPAM在TBI中促进再髓样的潜力的研究，这将确定基本的作用机理，从而为诊所中潜在使用O TPAM奠定了基础。