Glial Interactions in Premyelinating Oligodendrocyte Destruction

髓鞘形成前少突胶质细胞破坏中神经胶质细胞的相互作用

• 批准号: 8441015
• 负责人: JIANRONG LI
• 金额: $ 35.08万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8441015
• 关键词: Animal Model; Apoptotic; Astrocytes; Back; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Caring; Cell Death; Cells; Ceramides; Cerebral Palsy; Cerebrum; Cessation of life; Childhood; Chronic; Clinical; Cognitive deficits; Cyst; Demyelinating Diseases; Demyelinations; Diffuse; Disease; FDA approved; Feeds; Galactose Binding Lectin; Gestational Age; Grant; Homeostasis; Human; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Lesion; Life; Liquid Chromatography; Mass Spectrum Analysis; Membrane; Metabolism; Microglia; Microscopic; Modeling; Molecular; Monitor; Multiple Sclerosis; Mus; Neonatal; Neonatal Intensive Care; Neurologic; Oligodendroglia; Oxidants; Pathogenesis; Pathway interactions; Periventricular Leukomalacia; Peroxonitrite; Pharmaceutical Preparations; Play; Premature Birth; Premature Infant; Process; Production; Rattus; Research; Rodent Model; Role; Signal Pathway; Signal Transduction; Sphingolipids; Survivors; Testing; Therapeutic Intervention; Toxic effect; Toxin; Tumor Necrosis Factor-alpha; United States; astrogliosis; base; carbohydrate binding protein; cell injury; cytokine; disability; effective therapy; feeding; fetal infection; in vivo; inorganic phosphate; insight; intercellular communication; killings; myelination; new therapeutic target; novel; prevent; receptor; response; sphingosine 1-phosphate; tandem mass spectrometry; therapeutic development; white matter; white matter damage; white matter injury

DESCRIPTION (provided by applicant): Human periventricular leukomalacia (PVL) is the major form of cerebral white matter injury underlying cerebral palsy and a leading cause of chronic neurological deficits in survivors of premature birth. With advances in neonatal intensive care, diffuse white matter injury has emerged as the principle form of PVL, characterized by prominent activation of microglia and astrocytes, selective loss of premyelinating oligodendrocytes (preOLs) and disturbances in myelination. Inflammation in the immature brain is associated with hypoxia/ischemia and maternal/fetal infection. However, the mechanism by which it contributes to preOL destruction remains uncertain. We demonstrated previously that activated microglia directly kill preOLs through production of peroxynitrite and that astrocytes "switch" this preOL death mechanism to one dependent upon tumor necrosis factor (TNF). We subsequently found that reactive astrocytes in human PVL accumulate significant amounts of ceramide, a signaling sphingolipid with critical roles in cell death and inflammation, and that ceramide acts synergistically with TNF causing apoptotic death of preOLs through an astrocyte dependent mechanism. Moreover, astrocytes markedly promote TNF production by activated microglia. As TNF is generated in PVL, our results suggest that astrocytes play an important role in amplifying cytokine toxicity to preOLs, thereby augmenting diffuse white matter damage. Thus, in the previous grant cycle, we identified a novel, pathogenic process in which activated astrocytes and microglia act co-operatively in regulating preOL demise. In the renewal, we hypothesize that astrocytes amplify microglial proinflammatory responses through induction of galectin-9 and that disruption of ceramide metabolism in astrocytes predisposes preOLs to inflammatory destruction. Our specific aims are (1) to determine the function of galectin-9 in regulating microglia immune responses; (2) to determine the mechanism by which altered ceramide metabolism in astrocytes potentiates preOL injury; and (3) to investigate whether modulating sphingosine-1-phosphate signaling pathway confers protection in a rat model of PVL. We will use galectin-9 deficient mice to establish the function of galectin-9 in regulating CNS inflammatory responses. We will also employ liquid chromatography tandem mass spectrometry to monitor changes of bioactive sphingolipids under various experimental paradigms and identify specific sphingolipid pathways involved in preOL injury and protection. This project is likely to generate novel insights into the mechanism of preOL destruction, and will provide the framework for targeting specific sphingolipid signaling pathways for therapeutic interventions of white matter injury.

描述（由申请人提供）：人脑室周围白质软化症（PVL）是导致脑瘫的脑白色损伤的主要形式，也是早产幸存者慢性神经功能缺损的主要原因。随着新生儿重症监护的进展，弥漫性白色物质损伤已成为PVL的主要形式，其特征在于小胶质细胞和星形胶质细胞的显著活化、髓鞘形成前少突胶质细胞（preOL）的选择性损失和髓鞘形成障碍。未成熟脑中的炎症与缺氧/缺血和母体/胎儿感染有关。然而，它有助于preOL破坏的机制仍然不确定。我们以前证明，激活的小胶质细胞直接杀死前OL通过生产过氧亚硝酸盐和星形胶质细胞的“开关”这一前OL死亡机制依赖于肿瘤坏死因子（TNF）。我们随后发现，人PVL中的反应性星形胶质细胞积累了大量的神经酰胺，神经酰胺是一种在细胞死亡和炎症中具有关键作用的信号鞘脂，并且神经酰胺与TNF协同作用，通过星形胶质细胞依赖性机制引起前OL的凋亡性死亡。此外，星形胶质细胞显着促进激活的小胶质细胞产生TNF。由于TNF在PVL中产生，我们的研究结果表明星形胶质细胞在放大细胞因子对前OL的毒性中起重要作用，从而增加弥漫性白色物质损伤。因此，在上一个资助周期，我们确定了一个新的，致病的过程中，激活的星形胶质细胞和小胶质细胞的行为合作，在调节preOL死亡。在更新中，我们假设星形胶质细胞通过诱导半乳糖凝集素-9放大小胶质细胞促炎反应，并且星形胶质细胞中神经酰胺代谢的破坏使preOL易于发生炎性破坏。我们的具体目标是（1）确定半乳糖凝集素-9在调节小胶质细胞免疫反应中的功能;（2）确定星形胶质细胞中神经酰胺代谢改变增强前OL损伤的机制;（3）研究调节1-磷酸鞘氨醇信号通路是否在PVL大鼠模型中提供保护。我们将使用半乳糖凝集素-9缺陷小鼠来确定半乳糖凝集素-9在调节CNS炎症反应中的功能。我们还将采用液相色谱串联质谱法监测各种实验范式下生物活性鞘脂的变化，并确定参与前OL损伤和保护的特定鞘脂途径。该项目可能会产生对preOL破坏机制的新见解，并将 提供了靶向特定鞘脂信号通路的框架，用于白色物质损伤的治疗干预。