GSK3B AS A TARGET FOR PRO-NEURONAL SURVIVAL IN CNS NEURONS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在之前的预算期间，我们发现与最初的假设相反，ERK似乎并不直接调节GSK3β的活性。因此，我们决定改变项目的方向。内质网(ER)功能障碍是内质网氧化损伤或错误折叠的蛋白质在内质网中堆积导致内质网应激的结果。内质网应激诱导进化保守的未折叠蛋白反应，为恢复正常的内质网功能提供工具。此外，内质网应激可能导致细胞死亡。内质网应激是几种神经疾病的重要因素，包括慢性神经退行性疾病或中风。然而，其在创伤性脊髓损伤(SCI)后的病理演变中的作用目前尚不清楚。我们建议验证这一假设，即在脊髓损伤后，内质网应激通过诱导少突胶质细胞和少突胶质前体细胞的死亡来促进脱髓鞘。其具体目的包括：(1)分析脊髓挫伤后内质网应激标志物的表达；(2)分析内质网应激反应通路缺失突变小鼠的脊髓损伤结局；(3)鉴定培养的少突胶质细胞内源性内源性内源内源应激防御；(4)鉴定用于保护少突胶质细胞和改善内质网应激结局的抗内质网应激干预措施。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. During the previous budget period we revealed that contrary to the initial hypothesis, ERK does not seem to directly regulate GSK3beta activity. Therefore, we decided to change direction of the project. Endoplasmic reticulum (ER) dysfunction occurs as a result of oxidative damage to the ER or accumulation of misfolded proteins in that compartment leading to ER stress. ER stress induces an evolutionary conserved unfolded protein response that provides tools to restore the normal ER function. Also, ER stress may lead to cell death. The ER stress is an important player in several neurological disease including chronic neurodegenerative conditions or stroke. However, its contribution to the pathology that evolves after traumatic spinal cord injury (SCI) is unknown at present. We propose to test the hypothesis that after SCI, ER stress contributes to demyelination by inducing death of oligodendrocytes and oligodendrocyte precursor cells. The specific aims include (i) analysis of ER stress marker expression after contusion SCI, (ii) analysis of SCI outcome in mouse mutants deficient in ER stress response pathways, (iii) identification of endogenous ER stress defenses in cultured oligodendrocytes, (iv) identification of anti-ER stress interventions for oligodendrocyte protection and improvement of ER stress outcome.