INSULIN LIKE GROWTH FACTOR 1 ACTIONS IN OLIGODENDROCYTE

胰岛素样生长因子 1 在少突胶质细胞中的作用

• 批准号: 6188273
• 负责人: AUGUSTINE JOSEPH D'ERCOLE
• 金额: $ 24.8万
• 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 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6188273
• 关键词: antisense nucleic acid; apoptosis; biological signal transduction; brain injury; cysteine endopeptidases; gene induction /repression; genetically modified animals; growth factor receptors; insulinlike growth factor; laboratory mouse; myelin; nerve /myelin protein; nerve injury; nervous system regeneration; neuroprotectants; oligodendroglia; spinal cord injury; tissue /cell culture; transfection; tumor necrosis factor alpha

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.

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髓鞘再生是 对恢复至关重要。本申请的目的是确定 胰岛素样生长因子1（IGF-1）保护细胞的机制 少突胶质细胞谱系和髓鞘免受损伤并刺激其恢复 从受伤。研究者假设IGF-1保护少突胶质细胞 和髓磷脂，并促进损伤后的髓鞘再生。 此外，研究人员提出，IGF-1直接作用于细胞， 少突胶质细胞谱系通过1型IGF-1介导的机制 受体（IGFIR），并涉及细胞凋亡信号的抑制， 刺激生长和生存途径。申请人的假设是 支持：（1）脱髓鞘损伤诱导脑IGF-1基因 以与损伤时空相关的方式表达;（2）数据 显示IGF-1过表达转基因小鼠表现出显著增加， 髓鞘和髓鞘特异性蛋白mRNA丰度以及显著的 少突胶质细胞数量增加;（3）研究表明，IGF-1保护 培养的少突胶质细胞和髓鞘免受肿瘤坏死的损伤 因子（TNF-α），一种与MS和其他脱髓鞘 紊乱为了进一步了解IGF-1的作用及其机制， 保护少突胶质细胞和髓鞘免受损伤， 1）确定介导IGF-1作用的信号通路， 保护少突胶质细胞和髓鞘免受TNF-α 2引起的损伤） 证实IGF-1可防止TNF-α诱导的少突胶质细胞， IGF-1转基因小鼠与TNF-α杂交对体内髓鞘的损伤 转基因小鼠，然后评估少突胶质细胞的存活和功能;（3） 确定IGF-1对少突胶质细胞和髓鞘恢复的作用， 通过产生条件性表达IGF-1的转基因小鼠， 评估诱导的IGF-1过表达对少突胶质细胞的影响 （4）确定IGF-1是否对损伤后的细胞系和髓鞘起作用。 通过研究IGF-IR突变小鼠， 表达在少突胶质细胞中被特异性消除。