IGF-I Actions in Oligodendrocyte/Myelin Injury

描述(申请人提供)：少突胶质细胞丢失和脱髓鞘通常是中枢神经系统(CNS)疾病的主要后果，包括多发性硬化症(MS)、营养不良以及缺氧/缺血和创伤造成的损伤。因此，防止少突胶质细胞死亡和促进再髓鞘形成是中枢神经系统损伤后结构和功能恢复的关键。我们的最新数据和其他人的数据表明，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(IGF1R)的相互作用启动的，进而通过其对基因表达的调节来启动。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，在受到脱髓鞘损伤的啮齿动物中，IGF-I和IGF1R基因的表达被诱导，在时间和空间上与损伤相关。我们最近的研究进一步支持了这一假说，表明：a)IGF-I显著促进发育过程中的髓鞘形成，以及b)我们最初对携带IGF1R缺失的小鼠的初步研究表明，IGF-I的作用是通过与IGF1R的相互作用直接介导的。在这个应用中，我们建议定义IGF在体内对少突胶质细胞系细胞的直接作用。我们将：a)建立两个突变的小鼠模型，每个模型都特异地在少突胶质前体细胞或成熟的少突胶质细胞中钝化IGF1R的表达，以及b)在每个模型中，我们将评估少突胶质细胞在发育过程中的发育和髓鞘形成，以及少突胶质细胞系细胞对铜吡酮和缺血/缺氧损伤的反应。

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.