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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：
9773237
负责人：
MICHAEL V L BENNETT
金额：
$ 38.66万
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9773237
关键词：
Action Potentials Acute Alteplase Amino Acid Substitution Amino Acids Anti-Inflammatory Agents Antioxidants Axon Behavioral Binding Blood - brain barrier anatomy Brain Brain Edema Cause of Death Cell Differentiation process Cell Maturation 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 Impairment 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 PPAR alpha PPAR gamma Peptide Hydrolases Peroxisome Proliferator-Activated Receptors Plasminogen Activator Play Prevention therapy Process Proliferating Property Recovery Recovery of Function Reporting Reproducibility Research Risk Role Serine Protease Signal Transduction Structure System TBI treatment Testing Therapeutic Agents Time Traumatic Brain Injury Traumatic Brain Injury recovery axon regeneration axonal degeneration axonal sprouting base conditional knockout controlled cortical impact deprivation disability functional improvement gray matter improved in vivo knock-down mouse model mutant myelination nanomolar neglect neurological recovery neurorestoration novel oligodendrocyte precursor overexpression pre-clinical precursor cell public health relevance receptor remyelination repaired restoration thrombolysis transcription factor 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（由申请人提供）：白质（WM）损伤的特征是轴突变性和髓鞘丧失（脱髓鞘），对于创伤性脑损伤（TBI）后的长期功能缺陷很重要。中枢神经系统表现出有限的 WM 修复能力，例如轴突再生和髓鞘再生。在 TBI 后 WM 修复过程中，少突胶质细胞前体细胞 (OPC) 会活跃增殖。然而，许多新生成的 OPC 无法分化为成熟的髓磷脂。本申请将检查鼻内递送蛋白酶失活纤溶酶原激活剂突变体 (tPAm) 的效果，以增强少突细胞的分化和成熟，从而促进 TBI 后白质的完整性。产生少突胶质细胞（OL），导致髓鞘再生不足。髓鞘再生失败不仅会减少信号转导，还会导致轴突变性并使临床结果恶化。因此，促进 OPC 分化和成熟的干预措施是增强 WM 修复和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 FDA 批准的一种治疗缺血性中风的药物，通过丝氨酸蛋白酶作用催化溶栓。最近的研究发现 tPA 具有独立于蛋白酶活性的直接神经恢复作用。然而，tPA 作为 TBI 治疗剂的临床应用引起了一些担忧，因为它也会导致血脑屏障损伤和脑水肿。在本提案中，我们将探索蛋白酶失活突变体 tPA (tPAm)，通过替换单个氨基酸 (S478A) 来消除蛋白酶作用，作为一种新型恢复疗法，促进 TBI 后髓鞘再生和 WM 修复。我们发现纳摩尔浓度的 tPAm 促进培养的原代 OPC 分化为成熟的 OL。此外，tPA敲除会加剧TBI后持续至少35天的行为缺陷和WM损伤，而损伤后鼻内施用tPAm可改善小鼠TBI后的长期神经功能和WM完整性。初步数据进一步表明，tPAm 通过促进 OPC 分化和轴突髓鞘再生来增强 TBI 后的 WM 修复，并且该作用可能是由过氧化物酶体增殖物激活受体 γ (PPARγ) 核受体介导的。在这里，我们将重点关注 tPAm 的新型髓鞘再生作用，并检验以下假设：用蛋白酶失活的 tPAm 治疗至少部分地通过 PPARγ 激活诱导 OPC 分化和轴突髓鞘形成，促进 TBI 后 WM 修复和长期神经功能恢复。将测试三个具体目标。目标 1：确定 TBI 后 tPAm 治疗是否可以增强 WM 完整性并促进长期恢复。目标 2：检验 tPAm 诱导 OPC 分化/成熟并通过 PPAR 激活促进轴突髓鞘形成的假设。目标 3：检验以下假设：tPAm 诱导的 OPC 分化和轴突髓鞘形成对于保护 WM 完整性和 TBI 后的长期恢复至关重要。这些研究首次调查了 tPAm 在 TBI 中促进髓鞘再生的潜力，并将确定潜在的作用机制，从而为 tPAm 在临床中的潜在应用奠定基础。