Mechanisms of Death and Survival in Oligodendroglia

少突胶质细胞的死亡和生存机制

• 批准号: 7254073
• 负责人: Teresa L Wood
• 金额: $ 31.95万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-23 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254073
• 关键词: Mechanisms; Death; Survival; Oligodendroglia

DESCRIPTION (provided by applicant): Glutamate excitotoxicity has been implicated in loss of oligodendrocytes and their progenitors following ischemia and trauma and in demyelinating diseases. In particular, the progenitor stages of the lineage are most susceptible to many types of damage including excess glutamate. Studies both in vitro and in vivo have demonstrated that excess glutamate kills oligodendrocyte progenitors (OPs) via calcium influx through the AMPA/kainate receptors and that blockade of the AMPA/kainate receptors can protect oligodendrocyte progenitors from excess glutamate as well as from hypoxia-ischemia. Until recently, however, little was known about the mechanisms for glutamate-mediated toxicity. Our previous data demonstrated that excess glutamate leads to translocation of the pro-apoptotic Bcl family member Bax to the mitochondria, release of cytochrome c, activation of caspases 9 and 3 and death of oligodendrocyte progenitors. We also found that IGF-I has a unique ability to sustain activation of Akt and provide long-term protection of the oligodendrocyte progenitors from glutamate or trophic factor withdrawal, and that IGF-mediated survival in the presence of glutamate occurs downstream of calcium influx and upstream of Bax translocation and mitochondrial dysfunction. Thus, the goals of this proposal are to test the hypotheses that 1) glutamate toxicity of late OPs requires a Bax-mediated/mitochondrial pathway, which is activated through a calcium-induced cellular cascade, 2) IGF-I blocks Box-mediated mitochondrial dysfunction in OP cells through sustained IGF-IR/Akt signaling, and 3) perinatal H/I results in death of OPs through Box-mediated apoptosis, which can be blocked through activating Akt.

描述（由申请人提供）：谷氨酸兴奋性与少突胶质细胞及其祖细胞的丧失有关，其局部缺血和创伤以及脱髓鞘性疾病。特别是，谱系的祖细胞阶段最容易受到多种损害，包括多余的谷氨酸。在体外和体内的研究都表明，过量的谷氨酸通过AMPA/Kainate受体通过钙涌入杀死少突胶质细胞祖细胞（OPS），并且AMPA/Kainate受体的阻断可以保护过多的谷氨酸酸性元素以及从Hypoxia-IsChemia中保护过多的少突胶质细胞。然而，直到最近，对谷氨酸介导的毒性的机制知之甚少。我们先前的数据表明，过量的谷氨酸会导致促凋亡的BCl家族成员Bax转移到线粒体，细胞色素C的释放，胱天蛋白酶9和3的激活以及少突胶质细胞祖细胞的死亡。 We also found that IGF-I has a unique ability to sustain activation of Akt and provide long-term protection of the oligodendrocyte progenitors from glutamate or trophic factor withdrawal, and that IGF-mediated survival in the presence of glutamate occurs downstream of calcium influx and upstream of Bax translocation and mitochondrial dysfunction.因此，该提案的目标是测试以下假设：1）最近OPS的谷氨酸毒性需要一个Bax介导的/线粒体途径，该途径通过钙诱导的细胞级联激活，2）IGF-I通过盒子中介导的细胞通过op cellim and op cellim and-igf-ig-ig-ig-ig-i a和3在通过盒子介导的凋亡中OPS死亡中，可以通过激活Akt阻断。