PERK dependent mechanisms of neuroinflammation

神经炎症的 PERK 依赖性机制

• 批准号: 10629369
• 负责人: Gordon P. Meares
• 金额: --
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10629369
• 关键词: Affect; Area; Astrocytes; Attenuated; Biology; Blood flow; Brain; Brain region; CISH gene; Cell Death; Cell Survival; Cerebral Ischemia; Cerebrum; Cessation of life; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Endoplasmic Reticulum; Environment; Eukaryotic Initiation Factors; Future; Gene Expression; Genes; Genetic; Hour; Human; I Kappa B-Alpha; Impaired cognition; Infarction; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-6; Ischemia; Ischemic Stroke; JAK1 gene; Janus kinase; Knock-out; Knockout Mice; Mediating; Microglia; Middle Cerebral Artery Occlusion; Motor; Nerve Degeneration; Neuroglia; Neurons; Nutrient; Outcome; Oxygen; Pathway interactions; Persons; Phosphorylation; Phosphotransferases; Prevalence; Protein Inhibition; Protein Tyrosine Kinase; Protein-Serine-Threonine Kinases; Proteins; Reporting; Rodent; Role; Severities; Signal Transduction; Stroke; TNF gene; Testing; Therapeutic; Tissues; Translational Repression; Translations; United States; Wallerian Degeneration; Work; attenuation; biological adaptation to stress; blood-brain barrier permeabilization; cell injury; cognitive ability; conditional knockout; cytokine; disability; endoplasmic reticulum stress; functional outcomes; improved outcome; in vitro Model; in vivo; inhibitor; insight; ischemic injury; mouse model; nerve injury; neural model; neuroinflammation; neuron loss; neurotoxic; new therapeutic target; novel; preservation; prevent; protein kinase R; restoration; small molecule; stress kinase; stroke model; stroke outcome; synergism; therapeutic target; transcription factor

Abstract: Ischemic stroke affects a substantial number of people leading to long-term disability or death. Despite the prevalence of stroke, few treatment options are available. During an ischemic stroke, blood flow to a region of the brain is restricted preventing delivery of oxygen and essential nutrients. This leads to a complex environment within and around the infarcted tissue. This includes rapid cell death, inflammation, and endoplasmic reticulum (ER) stress in the surviving cells. The impact of ER stress on astrocytes and microglia and the resulting functional outcomes are unknown. ER stress activates the serine/threonine kinase protein kinase R-like ER kinase (PERK) which phosphorylates the eukaryotic initiation factor 2α (eIF2α) to attenuate protein translation. Our previous work has shown that PERK also activates the tyrosine kinase Janus kinase 1 (JAK1) to drive inflammatory gene expression. Additionally, our preliminary data show that PERK-dependent attenuation of protein translation enhances cytokine-induced inflammation in astrocytes and enhances neuronal death. Based on these findings, we hypothesize that PERK and JAK1 signaling contribute to worse stroke outcome and that targeting translational repression may provide therapeutic benefit. In this cycle, we will test this directly by deleting PERK in astrocytes and microglia to examine how PERK contributes to outcome in the stroke model of middle cerebral artery occlusion (MCAO). We will examine how translational suppression and JAK1 contribute to neuronal death and inflammation. Additionally, we will use the small molecule ISRIB to restore protein translation following MCAO to examine effects on functional outcome. We anticipate that deletion of PERK or restoration of protein translation will improve outcome following MCAO. Thus, identifying this signaling axis as a potential therapeutic target and furthering our understanding of glial biology.

抽象的： 缺血性中风会影响大量导致长期残疾或死亡的人。尽管 中风的患病率，几乎没有治疗选择。在缺血性中风期间，血液流向某个区域 大脑受到限制，以防止氧气和必需营养物质的递送。这导致了一个复杂的 梗塞组织内部和周围的环境。这包括快速细胞死亡，注射和 存活细胞中的内质网应激。 ER应力对星形胶质细胞和小胶质细胞的影响 所产生的功能结果尚不清楚。 ER应力激活丝氨酸/苏氨酸激酶蛋白 激酶R样ER激酶（PERK）磷酸化真核起始因子2α（EIF2α）减弱 蛋白质翻译。我们以前的工作表明，PERK还激活酪氨酸激酶Janus激酶1 （JAK1）驱动炎症基因表达。此外，我们的初步数据表明，PERK依赖性 蛋白质翻译的衰减增强了细胞因子诱导的星形胶质细胞注射并增强神经元 死亡。基于这些发现，我们假设PERK和JAK1信号导致中风较差 结果和靶向翻译表达可能会带来治疗益处。在这个周期中，我们将测试 直接通过删除星形胶质细胞和小胶质细胞的特权来检查振兴如何有助于结果 大脑中动脉闭塞的中风模型（MCAO）。我们将研究翻译抑制和 JAK1导致神经元死亡和炎症。此外，我们将使用小分子isrib恢复 MCAO后的蛋白质翻译检查对功能结果的影响。我们预计会删除 MCAO后，PERK或蛋白质翻译的恢复将改善结果。那，识别此信号 轴作为潜在的治疗靶标，并进一步了解我们对神经胶质生物学的理解。