Preconditioning brain white matter against ischemia

预处理脑白质以抵抗缺血

基本信息

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
项目类别：
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

项目摘要

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.

项目概要人口老龄化的增长以及中风护理的改善导致幸存者和中风患者的增加反复发生的缺血事件的增加，给负担过重的医疗经济带来了重大挑战这些病人。因此，诱导大脑对缺血的耐受性的方法已经获得了新的进展。临床和实验研究的势头。然而，缺血预适应（IPC）的机制尽管白质 (WM) 损伤和轴突功能障碍至关重要，但主要在灰质 (GM) 中进行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 体内模型均在啮齿类动物会出现短暂的缺氧/缺血，因此不适用于临床环境疗法。因此，建立临床适用的药理学方法来治疗疾病的需求尚未得到满足。预处理大脑以防止缺血。我们的初步结果表明 CX-4945 (Silmitasertib)，FDA- 批准的酪蛋白激酶 2 (CK2) 抑制剂，预处理 WM，促进轴突功能恢复并改善体外或体内缺血性损伤后的行为结果。尽管衰老会降低神经元 IPC，但 CX-4945 通过保留线粒体运动性，对年轻和衰老的 WM 进行相应预处理。因为门槛据报道，女性的先决条件更高，当前提案的主要目标是了解年轻和老年男性和女性 WM 中 CK2 抑制所赋予的预处理机制。我们报道了 CK2 通过 CDK5 和 AKT 途径发出信号来介导缺血性 WM 损伤。因此，CK2 抑制与少突胶质细胞、轴突结构和功能的保存以及年轻和老年 WM 中的线粒体动力学。我们的初步数据表明，短期的 CK2 抑制 CX-4945 通过维持线粒体运动有效地预处理轴突功能。此外， CX-4945 预处理可显着减轻体内局灶性损伤后观察到的行为缺陷皮质下 WM 损伤。我们发现 miR-501 是一种缺血上调的 miRNA，可被 CK2 抑制 miR-501 和 Miro-2 水平之间的抑制和相互作用调节轴突线粒体动力。与年龄和性别相比，中风患者血浆样本中 miR-501 水平有类似的上调匹配的对照建议 CK2 作为临床相关的治疗靶点。因此，我们建议延长这些通过测试我们的新假设进行研究，即 CK2 抑制通过差异调节 CDK5 来预处理 WM 和 AKT 信号通路通过相互调节 miR-501 和 Miro-2 维持线粒体动态水平。我们将结合电生理学、先进成像、线粒体功能分析、小鼠 miRNA 表达和调控研究、血浆中人类 miRNA 表达和人脑研究以及验证调节信号分子以确定 CK2 抑制是否通过 CDK5 或 AKT 发挥作用来调节通过改变 miRNA 谱来调节线粒体蛋白，以预防 WM 缺血。