ER stress and oligodendrocyte survival after spinal cord injury

描述(申请人提供)：内质网(ER)是细胞内的细胞器，分泌和膜蛋白在其中合成和折叠驻留的伴侣蛋白。内质网应激反应(ERSR)是一种进化保守的细胞防御机制，可防止错误折叠蛋白在内质网中过度积累。这些错误折叠的蛋白质通过内质网相关的降解度(ERAD)机制被转移到细胞质中，在那里它们被降解。ERSR在多种细胞应激后启动，包括缺氧、炎症、创伤、兴奋性毒性和氧化损伤。ERSR最初是保护性的，但如果错误折叠的蛋白质不能被清除，细胞就会开始凋亡。ERSR涉及的3条通路包括PERK、IRE1/XBP-1和ATF6信号通路。初步数据显示，脊髓损伤后，所有3条ERSR通路均上调。小鼠没有CHOP，这是一种位于PERK下游并在ERSR过程中激活的促凋亡转录因子，显示出脊髓损伤后功能恢复的增强，我们发现少突胶质细胞对内质网应激非常脆弱。我们假设，加强ERSR的保护或抑制凋亡方面将促进脊髓损伤后的功能恢复。在目标1中，我们将增强ERSR的保护效应，而在目标2中，我们将抑制那些启动少突胶质细胞凋亡的效应。我们将结合使用药理学药物、结构性和条件性缺失小鼠，以及使用野生型(WT)和可用的缺失少突胶质前体细胞(OPC)和/或siRNA进行的细胞培养研究来解决这些问题。 公共卫生相关性：脊髓损伤(SCI)对患者及其家人来说都是一种毁灭性的伤害，目前，无论是急性还是慢性患者，都没有有效的治疗方法。这项资助研究了内质网应激反应在脊髓损伤后每个脊髓细胞中诱导的一种细胞防御机制在调节脊髓损伤后髓鞘少突胶质细胞存活或死亡中的作用。我们期望确定新的急性治疗靶点，有望将其从脊髓损伤扩展到其他中枢神经系统创伤和神经疾病的治疗。

DESCRIPTION (provided by applicant): The endoplasmic reticulum (ER) is the intracellular organelle in which secretory and membrane proteins are synthesized and folded by resident chaperone proteins. The ER stress response (ERSR) is an evolutionarily conserved cell defense mechanism that protects against excessive accumulation of malfolded proteins in the ER. These malfolded proteins are translocated to the cytoplasm by the machinery of the ER- associated degredation (ERAD) where they are degraded. The ERSR is initiated after multiple cellular stresses including hypoxia, inflammation, trauma, excitotoxicity, and oxidative damage. The ERSR is initially protective, but if malfolded proteins cannot be cleared, apoptotic cell death initiates. The 3 pathways involved in the ERSR involve PERK, IRE1/XBP-1, and ATF6 signaling. Preliminary data demonstrate upregulation of all 3 ERSR pathways following SCI. Mice null for CHOP, a pro-apoptotic transcription factor that is downstream of PERK and activated during ERSR, showed enhanced functional recovery after SCI and we identified oligodendrocytes as highly vulnerable to ER stress. We hypothesize that enhancing the protective or inhibiting the apoptotic aspects of the ERSR will enhance functional recovery after SCI. In Aim 1, we will potentiate the protective effectors of ERSR and in Aim 2 suppress those that initiate oligodendrocyte apoptosis. We will use a combination of pharmacological agents, constitutive and conditional null mice, as well as cell culture studies using wild type (WT) and available null oligodendrocyte precursor cells (OPCs) and/or siRNAs to address these questions. PUBLIC HEALTH RELEVANCE: Spinal cord injury (SCI) is a devastating injury for both patients and their families and at present, there is no effective treatment, either acutely or for chronic patients. This grant examines the role of the endoplasmic reticulum stress response, a cellular defense mechanism induced in every spinal cord cell after SCI, in mediating survival or death of myelinating oligodendrocytes after SCI. We expect to identify new acute therapeutic targets that will hopefully extend beyond SCI to other CNS trauma and neurological disease treatment.