WNK1/OSR1 axis in Hippocampal Insulin Signaling, Glucose Metabolism and Age-related Cognitive Dysfunction

WNK1/OSR1 轴在海马胰岛素信号、葡萄糖代谢和年龄相关认知功能障碍中的作用

• 批准号: 10591443
• 负责人: Ankita Bachhawat Jaykumar
• 金额: $ 13.23万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10591443
• 关键词: 3xTg-AD mouse; Address; Age-associated memory impairment; Aging; Alzheimer' s Disease; Animal Model; Area; Behavior; Behavioral; Biochemistry; Biology; Brain; Cells; Cellular biology; Chronic; Cognition; Cognitive; Complement; Core Facility; Data; Dementia; Deterioration; Development; Disease; Down-Regulation; Environment; Exhibits; Female; Functional disorder; GLUT 4 protein; Glucose; Glucose Transporter; Goals; Hippocampus; Impaired cognition; Impairment; Institution; Insulin; Insulin Resistance; Insulin Signaling Pathway; Lysine; Mediating; Mediator; Memory; Mentors; Metabolic; Metabolic dysfunction; Metabolic syndrome; Metabolism; Modeling; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Neurons; Neurosciences; Oxidative Stress; Pathogenesis; Pharmacology; Phase; Phosphorylation; Phosphotransferases; Physiological; Physiology; Positioning Attribute; Process; Protein Kinase; Proto-Oncogene Proteins c-akt; Research; Risk Factors; Role; Signal Pathway; Signal Transduction; Synapses; Testing; Training; Transgenic Organisms; Vesicle; Work; age related; aging brain; career; cognitive function; cognitive process; glucose metabolism; glucose uptake; inhibitor; insulin signaling; male; memory process; mortality; mouse model; neurobehavioral; neuropathology; neurophysiology; neuropsychiatric symptom; sex; sexual dimorphism; skills; small hairpin RNA; sortilin; trafficking

Abstract This proposal aims to provide crucial training for my long-term career plan to examine WNK1/OSR1 signaling mechanisms contributing to neuronal metabolic alterations underlying the pathogenesis of age-related cognitive impairment in dementia. Alzheimer’s Disease (AD) is the leading age-related cause of dementia, characterized by progressive cognitive decline and neuropsychiatric symptoms. New research in animal models suggest that neuronal insulin resistance disrupts insulin signaling and glucose utilization by the hippocampal neurons that regulate cognition and contribute to pathogenesis of diseases such as AD. Yet, the exact molecular mediators regulating insulin signaling-mediated glucose uptake by the hippocampus and their roles in cognitive processes remain to be fully elucidated. I propose to investigate the contributions of protein kinases WNK1/OSR1 in hippocampal insulin signaling, sortilin-mediated glucose transporter-4 (GLUT4)-dependent glucose uptake and cognitive function. Although With-No-lysine (K) 1 (WNK1) and its substrate Oxidative Stress Responsive 1 (OSR1) are implicated in multiple diseases exhibiting cognitive and psychiatric impairments, the underlying mechanistic details involved are not known. My unpublished preliminary data highly suggest upregulated hippocampal WNK/OSR1 in cognitive deterioration via inhibition of insulin/AKT signaling, OSR1/sortilin- dependent GLUT4 trafficking and glucose uptake. My data also suggest negative WNK1-AKT crosstalk and disruption of this intricately controlled WNK1-AKT axis predisposes mice to metabolic dysfunction, which is reversed upon inhibition of WNK1 downstream signaling. Disruption of insulin/AKT signaling also underlies cognitive dysfunction in insulin resistant states in an age-dependent manner. These findings point to chronically enhanced hippocampal WNK1 signaling in the pathogenesis of cognitive deterioration in insulin resistant states and aging. I will test these hypotheses in this proposal. For this, I will acquire crucial training in insulin signaling pathways, neuroscience, behavioral physiology, and neuropathology during the K99 phase of this proposal to complement my previous training in metabolic pathophysiology, biochemistry, WNK1/OSR1 kinase biology, cell and molecular biology. I will be mentored by a leader in insulin signaling- Dr. Melanie Cobb, neuro-framework underlying metabolism and behavior- Dr. Jeffrey Zigman, molecular basis of memory- Dr. Kimberly Huber, synaptic trafficking- Dr. Ege T. Kavalali, aging and mechanisms of AD pathogenesis- Dr. Ilya Bezprozvanny. This proposal harnesses the commitment of the Peter O’ Donnell Jr. Brain Institute, Department of Neuroscience, Department of Pharmacology, Mouse Behavioral Core facility, and the overall scientific training environment of a world-class research institution at UTSW. Establishing a unique skill set in insulin and WNK1/OSR1 signaling pathway in addition to metabolism, neuroscience, behavioral physiology, and neuro-pathophysiology, will support my transition to an independent research academic position and will lead to the discovery of molecular mediators underlying neuronal metabolic disruption in age-related cognitive impairment in diseases such as AD.

摘要 这个建议旨在为我的长期职业计划提供关键的培训，以研究WNK 1/OSR 1信号 年龄相关认知功能障碍发病机制中神经元代谢改变的机制 痴呆症的损害。阿尔茨海默病（AD）是痴呆的主要年龄相关原因，其特征在于 进行性认知能力下降和神经精神症状动物模型的新研究表明， 神经元胰岛素抵抗破坏了海马神经元的胰岛素信号和葡萄糖利用， 调节认知并有助于疾病如AD的发病机制。然而，确切的分子介质 海马对胰岛素信号介导的葡萄糖摄取的调节及其在认知过程中的作用 还有待于充分阐明。我建议研究蛋白激酶WNK 1/OSR 1在 海马胰岛素信号，分拣蛋白介导的葡萄糖转运蛋白4（GLUT 4）依赖性葡萄糖摄取， 认知功能虽然无赖氨酸（K）1（WNK 1）及其底物氧化应激反应1（Oxidative Stress Responsive 1） （OSR 1）与表现出认知和精神障碍的多种疾病有关， 所涉及的机械细节尚不清楚。我未发表的初步数据高度表明 海马WNK/OSR 1通过抑制胰岛素/AKT信号传导，OSR 1/sortilin- 依赖GLUT 4运输和葡萄糖摄取。我的数据还表明负WNK 1-AKT串扰， 这种复杂控制的WNK 1-AKT轴的破坏使小鼠易于发生代谢功能障碍， 在抑制WNK 1下游信号传导后逆转。胰岛素/AKT信号传导的中断也是 胰岛素抵抗状态下的认知功能障碍，以年龄依赖的方式。这些发现表明， 增强的海马WNK 1信号在胰岛素抵抗状态下认知恶化发病机制中的作用 和衰老。我将在本提案中检验这些假设。为此，我将获得胰岛素信号的关键培训 途径，神经科学，行为生理学和神经病理学在K99阶段的这一建议， 补充我以前在代谢病理生理学，生物化学，WNK 1/OSR 1激酶生物学，细胞 和分子生物学。我将接受胰岛素信号传导领域的领导者-神经框架专家Melanie Cobb博士的指导 潜在的新陈代谢和行为-杰弗里·齐格曼博士，记忆的分子基础-金伯利·胡贝尔博士， 突触运输-Ege T. Kavalali，衰老和AD发病机制-Ilya Bezprozvanny博士。 这项建议利用了小彼得·奥唐奈的承诺。脑研究所，神经科学系， 药理学系，小鼠行为核心设施，以及 UTSW的世界级研究机构。建立胰岛素和WNK 1/OSR 1信号传导的独特技能集 除了代谢，神经科学，行为生理学和神经病理生理学之外， 支持我过渡到一个独立的研究学术立场，并将导致分子的发现 介导的神经元代谢破坏的年龄相关的认知障碍的疾病，如AD。