The integrated stress response and oligodendrocyte survival after spinal cord injury

抽象的。我们确定ER应激反应（ERSR）作为治疗干预的潜在靶点 对抗脊髓损伤（SCI）后的白色物质损失和运动障碍。具体来说，信号 涉及ERSR激酶PERK、PERK靶向延伸起始因子2α（eIF 2 α）和 PERK激活的转录因子CHOP可能以时间依赖性的方式被操纵以促进SCI。 复苏PERK信号传导与综合应激反应（ISR）有部分重叠，通过几个途径， 应激激活激酶，导致磷酸化eIF 2 α（peIF 2 α）水平升高，蛋白质的瞬时抑制 转录因子ATF 4的合成和激活。ATF 4调节CHOP以及参与CHOP的基因。 活性氧代谢、翻译调控和氨基酸合成。这样，ISR将尝试恢复 体内平衡ISR的过度和长期激活导致合成代谢相关的氧化应激， 线粒体损伤、细胞死亡和炎症。前ISR刺激，如缺氧，缺乏营养， 氧化应激和ER应激在SCI后存在。然而，主要ISR组件的作用- 除PERK以外的eIF 2 α激酶及其共同的下游靶点ATF 4-尚未在 挫伤性SCI后白色物质丢失的背景。我们的总体假设是ISR在 通过促进OL/OPC死亡和白色物质丢失在挫伤性SCI的发病机制中起作用。目标1将审查 4种上游ISR激酶（PERK、PKR、GCN 2、HRI，它们被不同的应激物激活）的作用， 磷酸化eIF 2 α，这反过来又抑制整体翻译，增强应激诱导的基因表达。 我们将使用先前优化的体外OPC/OL和体内SCI功能获得和丧失的组合 使用药理学抑制剂以及Hri-/-、Pkr-/-和Gcn 2-/-小鼠的试验。来自ER的初步数据 应激的OPC或SCI组织显示这些激酶的激活以及ISR的补偿性激活 当PERK被抑制时。目的2将研究中枢ISR效应子ATF 4在SCI中的作用。 相关的白色物质丢失。我们的初步数据显示，在SCI后或ER应激的OPC中，ATF 4被激活。 我们将确定ATF 4是否是OL/OPC死亡、白色物质损伤和功能下降的介导因子 挫伤性脊髓损伤后总之，目前的实验设计是基于我们以前的数据， SCI后ERSR的表征。在这里，我们建议描绘ISR介导的细胞凋亡的新机制， 以及确定哪些ISR介质最适合用于治疗转化， 急性脊髓损伤患者。这种治疗可能适用于其他类型的中枢神经系统创伤， TBI和中风

Abstract. We identified the ER stress response (ERSR) as a potential target for therapeutic interventions against white matter loss and locomotor impairment after spinal cord injury (SCI). Specifically, the signaling pathway that involves the ERSR kinase PERK, the PERK target elongation initiation factor 2α (eIF2α), and PERK-activated transcription factor CHOP may be manipulated in a time-dependent manner to promote SCI recovery. PERK signaling has a partial overlap with the integrated stress response (ISR) that, via several stress-activated kinases, leads to increased levels of phospho-eIF2α (peIF2α), transient inhibition of protein synthesis, and activation of the transcription factor ATF4. ATF4 regulates CHOP as well as genes involved in ROS metabolism, translational regulation and amino acid synthesis. In this way, the ISR attempts to restore homeostasis. Excessive and prolonged activation of the ISR results in anabolism-associated oxidative stress, mitochondrial damage, cell death and inflammation. Pro-ISR stimuli such as hypoxia, lack of nutrients, oxidative stress, and ER stress are present after SCI. However, the role of the principal ISR components – eIF2α kinases other than PERK and their common downstream target ATF4 – has not been addressed in the context of white matter loss after contusive SCI. Our overarching hypothesis is that the ISR plays a critical role in pathogenesis of contusive SCI by promoting OL/OPC death and white matter loss. Aim 1 will examine the role of the 4 upstream ISR kinases (PERK, PKR, GCN2, HRI, which are activated by different stressors) that phosphorylate eIF2α, which in turn inhibits global translation and enhances stress-induced gene expression. We will use a combination of previously optimized gain and loss of function in vitro OPC/OL and in vivo SCI assays that utilize pharmacological inhibitors as well as Hri-/-, Pkr-/-, and Gcn2-/-mice. Preliminary data from ER stressed OPCs or SCI tissue show activation of these kinases as well as compensatory activation of the ISR pathway when PERK is inhibited. Aim 2 will examine the role of the central ISR effector ATF4 in SCI- associated white matter loss. Our preliminary data show activation of ATF4 after SCI or in ER-stressed OPCs. We will determine whether ATF4 is a mediator of OL/OPC death, white matter damage, and functional decline after contusive SCI. In summary, current experimental design is based on data from our previous characterization of the ERSR after SCI. Here, we propose to delineate novel mechanisms of ISR-mediated cell death after SCI as well as define which of ISR mediators may best be suited for therapeutic translation to acutely treat SCI patients. Such treatments are likely to be applicable to other types of CNS trauma such as TBI and stroke.