INSULIN LIKE GROWTH FACTOR 1 ACTIONS IN OLIGODENDROCYTE

描述(改编自申请人的摘要)：少突胶质细胞和 它们产生的髓鞘容易受到各种疾病的影响 损伤，包括多发性硬化症(MS)、营养不良和缺血性 侮辱。预防少突胶质细胞死亡和促进再髓鞘形成是 对经济复苏至关重要。此应用程序的目标是确定 胰岛素样生长因子-1(IGF-1)保护心肌细胞的机制 少突胶质细胞谱系和髓鞘损伤并刺激其恢复 远离伤病。研究人员假设IGF-1保护少突胶质细胞 和髓鞘，并促进损伤后的再髓鞘形成。 此外，研究人员提出，IGF-1直接作用于血管内皮细胞。 IGF-1介导的少突胶质细胞谱系形成机制 受体(IGFIR)，参与抑制细胞凋亡信号和 刺激生长和生存途径。申请人的假设是 支持：(1)脱髓鞘侮辱可诱导脑IGF-1基因 在时间上与损伤相关的表达；(2)数据 显示过量表达IGF-1的转基因小鼠在 髓鞘和髓鞘特异蛋白mRNA的丰度以及显著的 少突胶质细胞数量的增加；以及(3)研究表明IGF-1具有保护作用 培养的少突胶质细胞和髓鞘对肿瘤坏死损伤的保护作用 与多发性硬化和其他脱髓鞘有关的细胞因子--肿瘤坏死因子-α 精神错乱。进一步了解胰岛素样生长因子-1的S作用及其机制 研究人员建议保护少突胶质细胞和髓鞘免受损害 目的：1)确定介导胰岛素样生长因子-1‘S作用的信号通路 保护少突胶质细胞和髓鞘免受肿瘤坏死因子-α2的损伤 确认IGF-1对肿瘤坏死因子-α诱导的少突胶质细胞和 IGF-1转基因小鼠体内髓鞘损伤的实验研究 转基因小鼠，然后评估少突胶质细胞的存活和功能； 确定胰岛素样生长因子-1‘S对少突胶质细胞和髓鞘修复的作用 产生有条件表达IGF-1和IGF-1的转基因小鼠造成的伤害 诱导IGF-1过表达对少突胶质细胞的影响 以及(4)确定IGF-1是否作用于 通过研究IGF-IR突变小鼠，少突胶质细胞和髓鞘是直接的 在少突胶质细胞中的表达被特异性地消融。

DESCRIPTION (Adapted from the applicant's abstract): Oligodendrocytes and the myelin sheaths that they produce are vulnerable to a variety of diseases and injuries, including multiple sclerosis (MS), undernutrition and ischemic insults. Prevention of oligodendrocyte death and promotion of remyelination are crucial to recovery. The object of this application is to determine the mechanisms by which insulin-like growth factor 1(IGF-1) protects cells of the oligodendrocyte lineage and myelin from damage and stimulates their recovery from injury. The investigator hypothesizes that IGF-1 protects oligodendrocytes and myelin from injury and promotes remyelination following injury. Furthermore, the investigator proposes that IGF-1 acts directly on cells of the oligodendrocyte lineage through mechanisms mediated by the type-1 IGF-1 receptor (IGFIR) and involving both inhibition of apoptosis signals and stimulation of growth and survival pathways. The applicant's hypotheses are supported by: (1) findings that demyelinating insults induce brain IGF-1 gene expression in a fashion temporospatially related to the injury; (2) the data showing that IGF-1 overexpressing transgenic mice exhibit marked increases in myelin and myelin-specific protein mRNA abundance as well as a significant increase in oligodendrocyte number; and (3) studies showing that IGF-1 protects cultured oligodendrocytes and myelin from the damage induced by tumor necrosis factor (TNF-alpha), a cytokine implicated in MS and other demyelinating disorders. To further understand IGF-1's actions and its mechanisms in protecting oligodendrocytes and myelin from damage the investigator proposes to: 1) determine the signaling pathways that mediate IGF-1's actions in protecting oligodendrocytes and myelin from injury caused by TNF-alpha 2) confirm that IGF-1 protects against TNF-alpha-induced oligodendrocyte and myelin injury in vivo by cross-breeding IGF-1transgenic mice to TNF-alpha transgenic mice and then evaluating oligodendrocyte survival and function; (3) determine IGF-1's actions on the oligodendrocytes and myelin recovery following injury by generating transgenic mice that conditionally express IGF-1 and evaluating the effects of induced IGF-1 overexpression on the oligodendrocyte lineage and myelin after injury; and (4) determine whether IGF-1 actions on oligodendrocytes and myelin are direct by studying mutant mice in whom IGF-IR expression is specifically ablated in oligodendrocytes.