ER stress and oligodendrocyte survival after spinal cord injury

脊髓损伤后内质网应激和少突胶质细胞存活

• 批准号: 8079910
• 负责人: MICHAL HETMAN
• 金额: $ 41.87万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079910
• 关键词: Acute; Address; Apoptosis; Apoptotic; Cell Culture Techniques; Cell Death; Cell Survival; Cells; Cellular Stress; Cessation of life; Chemicals; Chemosensitization; Chronic; Coculture Techniques; Commit; Cytoplasm; Cytoprotection; Data; Defense Mechanisms; Disease; Endoplasmic Reticulum; Family; Functional disorder; Genes; Genetic; Grant; Hand; Hypoxia; In Vitro; Inflammation; Injury; Knockout Mice; Locomotor Recovery; Mediating; Mediator of activation protein; Membrane Proteins; Methods; Modeling; Molecular Chaperones; Mus; Neurons; Oligodendroglia; Organelles; Pathology; Pathway interactions; Patients; Phosphorylation; Protein Dephosphorylation; Proteins; Recovery of Function; Role; Signal Transduction; Small Interfering RNA; Spinal Cord; Spinal Ganglia; Spinal cord injury; TNFRSF10B gene; Translational Repression; Translations; Trauma; Traumatic CNS injury; Tunicamycin; Up-Regulation; arm; biological adaptation to stress; cytotoxic; effective therapy; endoplasmic reticulum stress; excitotoxicity; improved; in vitro Assay; in vivo; inhibitor/antagonist; insight; loss of function; nervous system disorder; new therapeutic target; novel; oligodendrocyte precursor; oxidative damage; precursor cell; protective effect; research study; response; secretory protein; tauroursodeoxycholic acid; therapeutic target; transcription factor

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.

描述（由申请人提供）：内质网（ER）是细胞内细胞器，其中分泌和膜蛋白由居民伴侣蛋白合成并折叠。 ER应力反应（ERSR）是一种进化保守的细胞防御机制，可防止ER中碎蛋白过度积累。这些碎片蛋白通过降解的ER相关降解（ERAD）的机制将其转移到细胞质上。 ERSR是在多种细胞应激（包括缺氧，炎症，创伤，兴奋性毒性和氧化损伤）之后开始的。 ERSR最初具有保护性，但是如果无法清除碎片蛋白，则凋亡细胞死亡会引发。 ERSR中涉及的3个途径涉及PERK，IRE1/XBP-1和ATF6信号传导。初步数据证明了SCI后所有3个ERSR途径的上调。 CHOP的小鼠无效，这是一种促凋亡的转录因子，它是PERK的下游并在ERSR期间被激活的，在SCI后显示出增强的功能恢复，我们确定少突胶质细胞高度容易受到ER应力的影响。我们假设增强ERSR的保护性或抑制凋亡方面将增强SCI后的功能恢复。在AIM 1中，我们将增强ERSR的保护效应子，在AIM 2中抑制那些启动少突胶质细胞凋亡的效应。我们将结合使用野生型（WT）和可用的无少突胶质细胞前体细胞（OPC）和/或siRNA的药理学剂，组成型和条件无效小鼠以及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）是患者及其家人的毁灭性损伤，目前尚无有效的治疗，无论是急性或慢性病患者。该赠款研究了SCI后每个脊髓细胞中诱导的细胞防御机制的内质网应激反应的作用，在SCI后介导骨髓少突胶质细胞的存活或死亡中。我们希望确定新的急性治疗靶标，希望将SCI延伸到其他中枢神经系统创伤和神经系统疾病治疗。