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: 7210727
• 负责人: AUGUSTINE JOSEPH D'ERCOLE
• 金额: $ 35.25万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210727
• 关键词: Animals; Brain Hypoxia-Ischemia; Cell Surface Receptors; Cells; Central Nervous System Diseases; Cessation of life; Cuprizone; Data; Demyelinations; Development; Gene Expression Regulation; Hypoxia; IGF1R gene; Injury; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Receptor; Ischemia; Malnutrition; Mediating; Modeling; Multiple Sclerosis; Mus; Mutant Strains Mice; Myelin; Natural regeneration; Neuraxis; Oligodendroglia; Prevention; Recovery of Function; Rodent; Somatomedins; Structure; Trauma; central nervous system injury; in vivo; injury and repair; mutant mouse model; myelination; oligodendrocyte lineage; oligodendrocyte precursor; response

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，预防少突胶质细胞死亡和促进髓鞘再生对于中枢神经系统损伤后的结构和功能恢复至关重要。我们最近的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 (IGF1R) 的相互作用启动，进而通过其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，在遭受脱髓鞘损伤的啮齿类动物中，IGF-I和IGF1R基因的表达以与损伤在时间和空间上相关的方式被诱导。我们最近的研究进一步支持了这一假设，表明：a) IGF-I 在发育过程中显着促进髓鞘形成，b) 我们对成熟少突胶质细胞中携带 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。在此应用中，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）生成两个突变小鼠模型，每个模型的 IGF1R 表达均在少突胶质细胞前体或成熟少突胶质细胞中特异性减弱，b）在每个模型中，我们将评估发育过程中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铜宗和缺血/缺氧损伤的反应。

项目成果

Neurodevelopmental effects of insulin-like growth factor signaling.

• DOI: 10.1016/j.yfrne.2012.06.002
• 发表时间: 2012-08
• 期刊: FRONTIERS IN NEUROENDOCRINOLOGY
• 影响因子: 7.4
• 作者: O'Kusky, John;Ye, Ping
• 通讯作者: Ye, Ping

Tumor necrosis factor-alpha regulation of insulin-like growth factor-I, type 1 IGF receptor, and IGF binding protein expression in cerebellum of transgenic mice.

肿瘤坏死因子-α 对转基因小鼠小脑中胰岛素样生长因子-I、1 型 IGF 受体和 IGF 结合蛋白表达的调节。

• DOI: 10.1002/jnr.10512
• 发表时间: 2003
• 期刊: Journal of neuroscience research.
• 作者: Ye,Ping;Price,Wayne;Kassiotis,George;Kollias,George;D'Ercole,AJoseph
• 通讯作者: D'Ercole,AJoseph

Mouse NG2+ oligodendrocyte precursors express mRNA for proteolipid protein but not its DM-20 variant: a study of laser microdissection-captured NG2+ cells.

小鼠 NG2 少突胶质细胞前体表达蛋白脂质蛋白的 mRNA，但不表达其 DM-20 变体：一项对激光显微切割捕获的 NG2 细胞的研究。

• DOI: 10.1523/jneurosci.23-11-04401.2003
• 发表时间: 2003
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Ye,Ping;Bagnell,Robert;D'Ercole,AJoseph
• 通讯作者: D'Ercole,AJoseph

Signalling through the type 1 insulin-like growth factor receptor (IGF1R) interacts with canonical Wnt signalling to promote neural proliferation in developing brain.

• DOI: 10.1042/an20120009
• 发表时间: 2012-07-10
• 期刊: ASN neuro
• 影响因子: 4.7
• 作者: Hu Q;Lee SY;O'Kusky JR;Ye P
• 通讯作者: Ye P

Histone deacetylase 11 regulates oligodendrocyte-specific gene expression and cell development in OL-1 oligodendroglia cells.

• DOI: 10.1002/glia.20729
• 发表时间: 2009-01-01
• 期刊: GLIA
• 影响因子: 6.2
• 作者: Liu, Hedi;Hu, Qichen;D'Ercole, Joseph;Ye, Ping
• 通讯作者: Ye, Ping