IGF-I Actions in Oligodendrocyte/Myelin Injury

IGF-I 在少突胶质细胞/髓磷脂损伤中的作用

• 批准号: 6877984
• 负责人: AUGUSTINE JOSEPH D'ERCOLE
• 金额: $ 35.04万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6877984
• 关键词: cell differentiation; cell proliferation; cerebral ischemia /hypoxia; developmental neurobiology; electron microscopy; gene induction /repression; growth factor receptors; in situ hybridization; insulinlike growth factor; laboratory mouse; myelination; nerve /myelin protein; nerve injury; nervous system regeneration; oligodendroglia; polymerase chain reaction; southern blotting

DESCRIPTION (provided by applicant): Oligodendrocyte loss and demyelination are often major consequences of disorders of central nervous system (CNS), including multiple sclerosis (MS), undernutrition and injury from hypoxia/ischemia and trauma. Prevention of oligodendrocyte death and promotion of remyelination, therefore, are crucial to the structural and functional recovery of the CNS from injury. Our recent data and the data of others indicate that insulin-like growth factor-1 (IGF-I) is capable of protecting oligodendrocytes and myelination against injury and promoting regeneration of myelin following injury. We hypothesize that IGF-I acts directly on the cells of oligodendrocyte lineage by mechanisms that are initiated by interaction with its cell surface receptor, the type 1 IGF receptor (IGF1R), and in turn by its regulation of gene expression. Our hypothesis is supported by the evidence that IGF-I promotes proliferation and differentiation of cultured oligodendrocyte lineage cells. Furthermore in rodents subjected to demyelinating insults, the expression of IGF-I and IGF1R genes is induced in a fashion temporally and spatially related to the injury. Our recent studies further support the hypothesis by showing that: a) IGF-I significantly promotes myelination during development, and b) our initial studies of mice carrying an IGF1R null deletion specifically in mature oligodendrocytes demonstrate that IGF-I actions are directly mediated by interactions with the IGF1R. In this application, we propose to define IGF direct actions on cells of the oligodendrocyte lineage in vivo. We will: a) generate two mutant mouse models, each with blunted IGF1R expression specifically in oligodendrocyte precursors or in mature oligodendrocytes, and b) in each model we will evaluate oligodendrocyte development and myelination during development and the response of oligodendrocyte lineage cells to cuprizone and to ischemia/hypoxic injury.

描述（由申请人提供）：少突胶质细胞损失和脱髓鞘通常是中枢神经系统（CNS）疾病的主要后果，包括多发性硬化（MS）、营养不良和缺氧/缺血和创伤造成的损伤。因此，预防少突胶质细胞死亡和促进髓鞘再生对CNS损伤的结构和功能恢复至关重要。我们最近的数据和其他数据表明，胰岛素样生长因子-1（IGF-I）能够保护少突胶质细胞和髓鞘形成免受损伤，并促进损伤后髓鞘的再生。我们假设IGF-I直接作用于少突胶质细胞系的细胞，其机制是通过与其细胞表面受体，1型IGF受体（IGF 1 R）的相互作用而启动的，进而通过其基因表达的调节。我们的假设得到了IGF-I促进培养的少突胶质细胞系细胞增殖和分化的证据的支持。此外，在遭受脱髓鞘损伤的啮齿动物中，IGF-I和IGF 1 R基因的表达以与损伤时间和空间相关的方式被诱导。我们最近的研究进一步支持了这一假设，表明：a）IGF-I在发育过程中显著促进髓鞘形成，和B）我们对携带IGF 1 R无效缺失的小鼠的初步研究，特别是在成熟的少突胶质细胞中，表明IGF-I的作用是直接通过与IGF 1 R的相互作用介导的。在本申请中，我们建议定义IGF对体内少突胶质细胞谱系细胞的直接作用。我们将：a）产生两种突变小鼠模型，每一种在少突胶质细胞前体或成熟少突胶质细胞中特异性地具有钝化的IGF 1 R表达，和B）在每一种模型中，我们将评估发育期间的少突胶质细胞发育和髓鞘形成以及少突胶质细胞谱系细胞对cuprizone和对缺血/缺氧损伤的反应。