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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在上一个预算期间，我们发现与最初的假设相反，ERK似乎不直接调节GSK 3 β活性。因此，我们决定改变项目的方向。内质网（ER）功能障碍是由于ER的氧化损伤或错误折叠蛋白在该隔室中的积累导致ER应激而发生的。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了工具。此外，内质网应激可能导致细胞死亡。内质网应激是包括慢性神经退行性疾病或中风在内的几种神经系统疾病的重要参与者。然而，其对创伤性脊髓损伤（SCI）后病理演变的贡献目前尚不清楚。我们建议测试的假设，SCI后，ER应力有助于脱髓鞘诱导少突胶质细胞和少突胶质细胞前体细胞的死亡。具体目标包括（i）分析挫伤SCI后ER应激标志物的表达，（ii）分析ER应激反应途径缺陷的小鼠突变体的SCI结果，（iii）鉴定培养的少突胶质细胞中的内源性ER应激防御，（iv）鉴定用于少突胶质细胞保护和改善ER应激结果的抗ER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.