ER stress and oligodendrocyte survival after spinal cord injury

描述（由申请人提供）：内质网（ER）是细胞内的细胞器，分泌蛋白和膜蛋白在其中被伴侣蛋白合成和折叠。内质网应激反应（ERSR）是一种进化保守的细胞防御机制，可防止内质网中折叠不良蛋白的过度积累。这些折叠错误的蛋白质通过内质网相关降解（ERAD）的机制转运到细胞质中，在那里它们被降解。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最初具有保护作用，但如果折叠错误的蛋白不能被清除，细胞凋亡就会开始。ERSR中涉及的3条通路包括PERK、IRE1/XBP-1和ATF6信号。初步数据显示，脊髓损伤后所有3条ERSR通路均上调。CHOP是一种促凋亡转录因子，位于PERK的下游，在ERSR期间被激活。CHOP缺失的小鼠在脊髓损伤后显示出增强的功能恢复，我们发现少突胶质细胞对内质网应激非常脆弱。我们假设增强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Aim 1中，我们将增强ERSR的保护效应，在Aim 2中，我们将抑制那些启动少突胶质细胞凋亡的保护效应。为了解决这些问题，我们将联合使用药物、组成型和条件型小鼠，以及使用野生型（WT）和可用的空少突胶质前体细胞（OPCs）和/或sirna进行细胞培养研究。

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.