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White matter protection by inhibitors of glial scar formation in perinatal hypoxia ischemia

围产期缺氧缺血时胶质疤痕形成抑制剂对白质的保护作用

基本信息

批准号：
10608122
负责人：
Stephen Arthur Back
金额：
$ 36.19万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608122
关键词：
Adult Animal Model Astrocytes Attention Attenuated Blocking Antibodies Brain Brain Hypoxia-Ischemia Cerebral Palsy Cerebrum Childhood Chronic Cicatrix Clinical Trials Cognitive Diagnosis Diffuse Disease Enzymes Event Extracellular Matrix Failure Future Generations Genes Human Hyaluronic Acid Hyaluronidase In Vitro Learning Lesion Life Mediating Memory Modeling Molecular Motor Natural regeneration Neonatal Pathway interactions Perinatal Hypoxia Phase Premature Birth Proliferating Protein Subunits Proteins Reaction Risk Rodent Role Signal Transduction Socialization Survivors TNF gene Testing Therapeutic Time Tumor Necrosis Factor Activation Vertebral column astrocyte progenitor astrogliosis central nervous system injury connectome disability hypoxic ischemic injury in vivo inhibiting antibody inhibitor insight inter-alpha-inhibitor kinase inhibitor myelination nervous system disorder neurobehavioral neuropsychiatric disorder novel novel strategies novel therapeutic intervention novel therapeutics oligodendrocyte progenitor preterm newborn prevent progenitor protein complex repaired response src-Family Kinases white matter white matter injury

项目摘要

Project Summary Survivors of preterm birth are commonly diagnosed with persistent white matter injury (WMI) that leads to a failure of normal myelination. Myelination failure results in life long motor and neurobehavioral disabilities. The central feature of WMI is the so-called “glial scar,” an inhibitory barrier generated by reactive astrocytes, which causes myelination failure by blocking the maturation of oligodendrocyte progenitors. It is our long-term objective to develop novel therapies to prevent myelination failure by preventing glial scar formation. There are no therapeutic strategies to prevent early formation of diffuse reactive astrogliosis before it chronically blocks myelination. WMI disrupts the integrity of the hyaluronic acid (HA) backbone of the extracellular matrix. We have defined a novel pathway through which small ~5 kDa HA oligomers (HA5) regulate the proliferation of astroglial progenitors and promote reactive astrogliosis. Through the enzyme tumor necrosis factor- (TNF) stimulated gene-6 (TSG-6), HA5 serves as a sink that traps heavy chain (HC) protein subunits of the inter-alpha-inhibitor protein (II) complex. This reaction generates unstable intermediates of II that release HC. We have identified novel approaches to block this TSG-6-dependent pathway to markedly attenuate the formation of the glial scar. Our over-riding hypothesis is that HA5-mediated HC release promotes reactive astrogliosis via a src family kinase-dependent pathway. We propose three specific aims to test this hypothesis. In aim 1, we hypothesize that hyaluronidase activation in the glial scar promotes the formation of HA5. We will determine the hyaluronidases (HYAL) that generate HA5 to promote formation of the glial scar and determine if a broad spectrum HYAL inhibitor reduces astrogliosis in response to WMI. In aim 2, we will test the hypothesis that HA5 promotes astrocyte proliferation and reactive astrogliosis through TSG-6-dependent release of heavy chains derived from II. We will determine if astrocyte proliferation in WMI is dependent on TSG-6 expression that promotes astrogliosis in vitro and in vivo via an HC-dependent mechanism. In aim 3, we hypothesize that activation of TSG-6 mediates glial scar formation via activation of src family kinases. We will first determine if a TSG-6 blocking antibody inhibits proliferation of astrocyte progenitors in vivo. We will test a src kinase inhibitor, currently in clinical trials, as a novel strategy to block glial scar formation and promote myelination. At the conclusion of these studies, we expect to define new therapeutic strategies to intervene during early WMI to prevent formation of the glial scar and promote myelination. Given that reactive astrogliosis is a central feature of many forms of CNS injury, our findings may have potential benefit for other pediatric and adult neurological disorders with prominent WMI.

项目概要早产幸存者通常被诊断患有持续性脑白质损伤 (WMI)，这会导致正常髓鞘形成失败。髓鞘形成失败会导致终生运动和神经行为障碍。这 WMI 的核心特征是所谓的“神经胶质疤痕”，这是一种由反应性星形胶质细胞产生的抑制性屏障，通过阻止少突胶质细胞祖细胞的成熟导致髓鞘形成失败。这是我们的长期目标目标是开发新疗法，通过预防神经胶质疤痕形成来预防髓鞘形成失败。没有治疗策略可以预防弥漫性反应性星形胶质细胞增生的早期形成长期阻碍髓鞘形成。 WMI 破坏细胞外基质透明质酸 (HA) 主链的完整性。我们定义了一个小〜5 kDa HA寡聚体（HA5）调节星形胶质细胞增殖的新途径祖细胞并促进反应性星形胶质细胞增生。通过酶瘤坏死因素- (肿瘤坏死因子) 受刺激的基因 6 (TSG-6)，HA5 作为一个接收器，捕获内部 α 抑制剂的重链 (HC) 蛋白亚基蛋白质 (II) 复合物。该反应生成不稳定的 II 中间体并释放 HC。我们有确定了阻断这种 TSG-6 依赖性途径的新方法，以显着减弱胶质疤痕。我们最重要的假设是 HA5 介导的 HC 释放促进反应性星形胶质细胞增生通过 src 家族激酶依赖性途径。我们提出了三个具体目标来检验这一假设。瞄准目标如图1所示，我们假设神经胶质疤痕中透明质酸酶的激活促进了HA5的形成。我们将确定产生 HA5 以促进神经胶质疤痕形成的透明质酸酶 (HYAL)，并确定是否广谱 HYAL 抑制剂可减少 WMI 引起的星形胶质细胞增生。在目标 2 中，我们将测试 HA5 通过 TSG-6 依赖性促进星形胶质细胞增殖和反应性星形胶质细胞增生的假设释放源自 II 的重链。我们将确定 WMI 中的星形胶质细胞增殖是否依赖于 TSG-6 表达通过 HC 依赖性机制在体外和体内促进星形胶质细胞增生。在目标 3 中，我们假设 TSG-6 的激活通过 src 家族激酶的激活介导神经胶质疤痕的形成。我们首先确定 TSG-6 阻断抗体是否抑制体内星形胶质细胞祖细胞的增殖。我们将测试目前正在进行临床试验的 src 激酶抑制剂，作为阻止神经胶质疤痕形成的新策略促进髓鞘形成。在这些研究结束时，我们期望定义新的治疗策略在早期 WMI 期间进行干预，以防止神经胶质疤痕的形成并促进髓鞘形成。鉴于反应性星形胶质细胞增生是多种中枢神经系统损伤的核心特征，我们的研究结果可能对其他疾病有潜在的益处具有显着 WMI 的儿童和成人神经系统疾病。