Preconditioning brain white matter against ischemia

预处理脑白质以抵抗缺血

• 批准号: 10680844
• 负责人: Selva Baltan
• 金额: $ 59.11万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680844
• 关键词: 3-Dimensional; AKT Signaling Pathway; Age; Aging; Attenuated; Axon; Behavior assessment; Behavioral; Bioinformatics; Brain; Brain Hypoxia-Ischemia; CDK5 gene; Cancer Patient; Caring; Cause of Death; Clinical; Clinical Research; Common carotid artery; Correlation Studies; Cyclic AMP-Dependent Protein Kinases; Data; Electron Microscopy; Electrophysiology (science); Event; FDA approved; Female; Functional disorder; Funding; Genus Hippocampus; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Human; Image; In Vitro; Ischemia; Ischemic Preconditioning; Mediating; MicroRNAs; Mitochondria; Mitochondrial Proteins; Modeling; Mus; Neurologic; Neurons; Oligodendroglia; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma; Proto-Oncogene Proteins c-akt; Recovery of Function; Recurrence; Regulation; Reporting; Risk; Rodent; Role; Sampling; Signal Transduction; Signaling Molecule; Stroke; Structure; Survivors; Testing; Therapeutic; Translating; Up-Regulation; Validation; aging population; artery occlusion; axon injury; behavioral outcome; casein kinase II; cell motility; clinical application; clinically relevant; disability; experimental study; gray matter; health care economics; high risk; improved; in vivo; in vivo Model; inhibitor; ischemic injury; male; novel; pharmacologic; preconditioning; preservation; protective effect; sex; spatiotemporal; stroke event; stroke patient; stroke survivor; subcortical ischemic vascular disease; therapeutic target; trafficking; white matter; white matter injury

PROJECT SUMMARY A growth in the aging population together with improved stroke care has resulted in an increase in survivors and a rise in recurrent ischemic events, presenting major challenges for overburdened healthcare economics for these patients. Consequently, approaches to induce tolerance in the brain against ischemia have gained new momentum in clinical and experimental studies. However, mechanisms of ischemic preconditioning (IPC) have been primarily studied in gray matter (GM), despite white matter (WM) injury and axon dysfunction being critical components of clinical deficits observed in stroke patients. Moreover, most in vivo models of IPC performed in rodents consist of short episodes of hypoxia/ischemia and are not applicable to translate into clinical settings as therapeutics. Therefore, there is an unmet need to establish clinically applicable pharmacological approaches to preconditioning the brain against ischemia. Our preliminary results show that CX-4945 (Silmitasertib), an FDA- approved Casein Kinase 2 (CK2) inhibitor, preconditions WM, promotes axon function recovery and improves behavioral outcomes after an in vitro or in vivo ischemic injury. Although aging reduces neuronal IPC, CX-4945 comparably preconditions young and aging WM by preserving mitochondrial motility. Because the threshold to precondition is reported to be higher in females, the main goal of this current proposal is to understand the mechanisms of preconditioning conferred by CK2 inhibition in young and aging male and female WM. We have reported that CK2 signals via the CDK5 and AKT pathways to mediate ischemic WM injury. Thus, CK2 inhibition correlates with the preservation of oligodendrocytes, axon structure and function, and conservation of mitochondrial dynamics in young and aging WM. Our preliminary data show that a brief period of CK2 inhibition with CX-4945 effectively preconditions axon function by maintaining mitochondrial motility. Furthermore, preconditioning with CX-4945 considerably attenuates behavioral deficits observed after an in vivo focal subcortical WM injury. We identified miR-501 as an ischemia-upregulated miRNA that is suppressed by CK2 inhibition, and reciprocal interaction between levels of miR-501 and Miro-2 regulates axonal mitochondrial motility. A similar upregulation of miR-501 levels in stroke patient plasma samples compared to age- and sex- matched controls propose CK2 as a clinically relevant therapeutic target. Therefore, we propose to extend these studies by testing our novel hypothesis that CK2 inhibition preconditions WM by differentially regulating the CDK5 and AKT signaling pathways to maintain mitochondrial dynamics by reciprocally regulating miR-501 and Miro-2 levels. We will combine electrophysiology, advanced imaging, functional analysis of mitochondria, mouse miRNA expression and regulation studies, human miRNA expression in plasma and human brain studies, and validation of regulated signaling molecules to determine whether CK2 inhibition acts via CDK5 or AKT to regulate mitochondrial proteins through alteration of miRNA profiles to precondition WM against ischemia.

项目摘要 老龄化人口的增长以及卒中护理的改善导致了幸存者的增加， 复发性缺血事件的增加，为负担过重的医疗保健经济带来了重大挑战， 这些病人。因此，在脑中诱导针对缺血的耐受性的方法已经获得了新的进展。 在临床和实验研究的势头。然而，缺血预处理（IPC）的机制， 尽管白色物质（WM）损伤和轴突功能障碍是关键的，但主要在灰质（GM）中进行了研究 在中风患者中观察到的临床缺陷的组成部分。此外，大多数IPC的体内模型在 啮齿类动物包括短暂的缺氧/缺血发作，不适用于转化为临床环境， 治疗学因此，需要建立临床上适用的药理学方法， 使大脑预处理以防止缺血。我们的初步结果表明，CX-4945（Silmitasertib），一种FDA- 批准的酪蛋白激酶2（CK 2）抑制剂，预处理WM，促进轴突功能恢复， 体外或体内缺血性损伤后的行为结果。尽管衰老减少了神经元IPC，但CX-4945 通过保留线粒体运动性，可以相对地为年轻和衰老的WM提供先决条件。因为 据报道，女性的先决条件更高，当前提案的主要目标是了解 CK 2抑制在年轻和老年男性和女性WM中赋予的预处理机制。 我们已经报道了CK 2信号通过CDK 5和AKT途径介导缺血性WM损伤。因此，CK 2 抑制与少突胶质细胞的保存、轴突结构和功能以及 年轻和衰老WM中的线粒体动力学。我们的初步数据显示，CK 2抑制的短暂时间 CX-4945通过维持线粒体运动有效地预处理轴突功能。此外，委员会认为， CX-4945预处理显著减弱了体内局灶性脑缺血后观察到的行为缺陷 皮质下WM损伤。我们将miR-501鉴定为缺血上调的miRNA，其被CK 2抑制。 抑制，以及miR-501和Miro-2水平之间的相互作用调节轴突线粒体 能动性与年龄和性别相比，中风患者血浆样本中miR-501水平的上调相似， 匹配的对照提出CK 2作为临床相关的治疗靶点。因此，我们建议延长这些 通过验证我们的新假设，即CK 2抑制通过差异调节CDK 5来预处理WM， 和AKT信号通路通过miR-501和Miro-2的调节来维持线粒体动力学 程度.我们将结合联合收割机电生理学、先进的成像技术、线粒体功能分析、小鼠miRNA 表达和调控研究，人miRNA在血浆和人脑中的表达研究，以及验证 以确定CK 2抑制是否通过CDK 5或AKT来调节 线粒体蛋白通过改变miRNA谱来预处理WM对抗缺血。