Mechanisms of Death and Survival in Oligodendroglia

少突胶质细胞的死亡和生存机制

• 批准号: 7450794
• 负责人: Teresa L Wood
• 金额: $ 33.12万
• 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/7450794
• 关键词: Adult; Apoptosis; Apoptotic; Boxing; Brain Hypoxia-Ischemia; Calcium; Cell Death; Cell membrane; Cells; Cessation of life; Condition; Data; Demyelinating Diseases; Demyelinations; Disease; Family member; Glutamates; Goals; In Vitro; Insulin-Like Growth Factor I; Ischemia; Kainic Acid Receptors; Mediating; Mitochondria; Modeling; Multiple Sclerosis; Neuraxis; Oligodendroglia; Pathology; Pathway interactions; Perinatal; Perinatal Hypoxia; Personal Satisfaction; Publishing; Recovery of Function; Recycling; Research; Signal Transduction; Spinal cord injury; Staging; Stem cells; Testing; Toxic effect; Trauma; Withdrawal; caspase-9; cytochrome c; excitotoxicity; in vivo; killings; mitochondrial dysfunction; oligodendrocyte lineage; prevent; progenitor; programs; receptor; receptor recycling; therapy design; white matter damage

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）：谷氨酸兴奋性毒性与缺血和创伤后少突胶质细胞及其祖细胞的损失以及脱髓鞘疾病有关。特别是，谱系的祖细胞阶段最容易受到许多类型的损伤，包括过量的谷氨酸。体外和体内研究均表明，过量的谷氨酸通过AMPA/红藻氨酸受体的钙内流杀死少突胶质细胞祖细胞（OP），并且阻断AMPA/红藻氨酸受体可以保护少突胶质细胞祖细胞免受过量谷氨酸以及缺氧缺血的影响。然而，直到最近，人们对谷氨酸介导的毒性机制知之甚少。我们以前的数据表明，过量的谷氨酸导致促凋亡Bcl家族成员Bax易位到线粒体，细胞色素c的释放，半胱天冬酶9和3的激活和少突胶质细胞祖细胞的死亡。我们还发现IGF-I具有独特的能力来维持Akt的激活，并为少突胶质细胞祖细胞提供长期保护，使其免受谷氨酸或营养因子戒断的影响，并且在谷氨酸存在下，IGF-I介导的存活发生在钙内流的下游和上游Bax易位和线粒体功能障碍。因此，本提案的目的是检验以下假设：1）晚期OP的谷氨酸毒性需要通过钙诱导的细胞级联激活的Box介导的/线粒体途径，2）IGF-I通过持续的IGF-IR/Akt信号传导阻断OP细胞中Box介导的线粒体功能障碍，和3）围产期H/I通过Box介导的细胞凋亡导致OP死亡，其可通过激活Akt而被阻断。