ER stress and oligodendrocyte survival after spinal cord injury

描述（由申请人提供）：内质网（ER）是细胞内细胞器，其中分泌蛋白和膜蛋白由常驻伴侣蛋白合成和折叠。ER应激反应（ERSR）是一种进化上保守的细胞防御机制，可防止错误折叠蛋白在ER中过度积累。这些错误折叠的蛋白质通过ER相关降解（ERAD）机制移位到细胞质中，在细胞质中它们被降解。ERSR在多种细胞应激（包括缺氧、炎症、创伤、兴奋性毒性和氧化损伤）后启动。ERSR最初是保护性的，但如果错误折叠的蛋白质不能被清除，则启动凋亡性细胞死亡。ERSR中涉及的3条通路涉及PERK、IRE 1/XBP-1和ATF 6信号传导。初步数据表明SCI后所有3种ERSR途径均上调。CHOP是一种促凋亡转录因子，位于PERK的下游，在ERSR过程中被激活，对CHOP无效的小鼠在SCI后表现出增强的功能恢复，我们发现少突胶质细胞对ER应激非常脆弱。我们推测增强ERSR的保护或抑制其凋亡方面将增强SCI后的功能恢复。在目标1中，我们将增强ERSR的保护效应，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。我们将使用药理学试剂、组成型和条件无效小鼠的组合，以及使用野生型（WT）和可用的无效少突胶质细胞前体细胞（OPC）和/或siRNA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，目前还没有有效的治疗方法，无论是急性还是慢性患者。这项资助研究了内质网应激反应的作用，一种在SCI后每个脊髓细胞中诱导的细胞防御机制，在SCI后介导髓鞘生成少突胶质细胞的存活或死亡。我们期望确定新的急性治疗靶点，有望从SCI扩展到其他CNS创伤和神经系统疾病的治疗。

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.