Mechanism of IGF-I actions on oligodendroglial cells

IGF-I对少突胶质细胞的作用机制

• 批准号: 6804321
• 负责人: AUGUSTINE JOSEPH D'ERCOLE
• 金额: $ 34.37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804321
• 关键词: biological signal transduction; cell differentiation; cell proliferation; chromatin; gene expression profiling; gene induction /repression; genetically modified animals; growth factor receptors; insulinlike growth factor; laboratory mouse; laser capture microdissection; microarray technology; nerve stem cell; neurogenesis; neurons; oligodendroglia; polymerase chain reaction; tissue /cell preparation

DESCRIPTION (provided by applicant): Increasing evidence indicates that insulin-like growth factor-I (IGF-I) plays an important role in the development of neural cells in the central nervous system, including oligodendrocyte lineage cells and myelination, as well as promoting regeneration of oligodendrocyte lineage cells 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 regulation of gene expression. Our hypothesis is supported by our data and those of others showing that: 1) IGF-I promotes proliferation and differentiation of oligodendrocyte lineage cells in culture; 2) overexpression of IGF-I in transgenic (Tg) mice during postnatal development increases the number of oligodendrocyte lineage cells; 3) in animals subjected to demyelinating insults, the expression of IGF-I and IGF1R genes is induced in a fashion temporally and spatially related to the injury; 4) IGF-I protects myelination from a variety of CNS injury; and 5) blunting IGFIR expression specifically in oligodendrocytes results in brain retardation and hypomyelination in the mutant mice. Furthermore, our recent studies show that IGF-I regulates multiple gene expression and modification of histone proteins in cells of oligodendrocyte line. In this application, we propose two specific aims to further examine our hypotheses: 1) To determine IGF actions on the development of oligodendrocyte precursors in vivo, we will examine oligodendrocyte precursors in newly developed Tg mice that overexpress IGF-I during embryonic and early postnatal development, and in mutant mice in which IGF1R expression is specifically blunted in oligodendrocyte precursors. 2) To delineate IGF-I signaling mechanisms leading to the gene regulation that promotes oligodendrocyte development, we will determine a) IGF-I in vivo regulation of global gene expression in oligodendrocytes and their precursors using laser captured microdissection and DNA array; and b) IGF-I actions on chromatin remodeling.

描述（由申请人提供）：越来越多的证据表明，胰岛素样生长因子- i （IGF-I）在中枢神经系统神经细胞的发育中起重要作用，包括少突胶质细胞和髓鞘形成，以及促进损伤后少突胶质细胞的再生。我们假设IGF- i通过与其细胞表面受体（1型IGF受体（IGF1R））相互作用启动的机制直接作用于少突胶质细胞谱系的细胞，并反过来通过调节基因表达。我们的假设得到了我们和其他人的数据的支持，这些数据表明：1)IGF-I促进培养的少突胶质细胞谱系细胞的增殖和分化；2)转基因（Tg）小鼠出生后发育过程中igf - 1的过表达增加了少突胶质细胞系细胞的数量；3)在脱髓鞘损伤的动物中，IGF-I和IGF1R基因的表达与损伤的时间和空间相关；4) igf - 1保护髓鞘形成免受多种中枢神经系统损伤；5) IGFIR在少突胶质细胞中的特异性表达减弱导致突变小鼠脑发育迟缓和髓鞘发育低下。此外，我们最近的研究表明，igf - 1调节少突细胞系细胞中多个基因的表达和组蛋白的修饰。在这个应用中，我们提出了两个具体的目标来进一步检验我们的假设：1)为了确定IGF在体内对少突胶质细胞前体发育的作用，我们将在胚胎和出生后早期发育期间过度表达IGF- i的新发育的Tg小鼠和IGF1R在少突胶质细胞前体中表达特异性减弱的突变小鼠中检测少突胶质细胞前体。2)为了描述IGF-I信号传导机制导致促进少突胶质细胞发育的基因调控，我们将利用激光捕获的显微解剖和DNA阵列来确定a) IGF-I在体内调控少突胶质细胞及其前体的整体基因表达；b) IGF-I对染色质重塑的作用。