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

摘要 这项提议旨在为我的长期职业计划提供关键的培训，以检查WNK1/OSR1信号 增龄性认知障碍发病机制中神经元代谢改变的研究 痴呆症的损害。阿尔茨海默病(AD)是与年龄相关的痴呆症的主要原因，特点是 由渐进性认知衰退和神经精神症状引起。对动物模型的最新研究表明 神经元胰岛素抵抗扰乱海马神经元对胰岛素信号和葡萄糖的利用 调节认知，参与阿尔茨海默病等疾病的发病。然而，确切的分子介体 海马体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 仍有待充分阐明。我建议研究蛋白激酶WNK1/OSR1在脑内的作用 海马胰岛素信号、山梨素介导的葡萄糖转运体-4依赖的葡萄糖摄取和 认知功能。尽管有-非赖氨酸(K)1(WNK1)及其底物氧化应激反应1 (OSR1)与多种疾病有关，表现出认知和精神障碍，潜在的 所涉及的机械细节尚不清楚。我未公布的初步数据高度暗示 海马WNK/OSR1通过抑制胰岛素/AKT信号通路、OSR1/Sortilin-1参与认知功能减退 依赖GLUT4转运和葡萄糖摄取。我的数据还表明WNK1-AKT串扰为负 这一复杂控制的WNK1-AKT轴的中断使小鼠容易出现代谢功能障碍，这是 WNK1下游信号被抑制后逆转。胰岛素/AKT信号转导中断也是基础 胰岛素抵抗状态下的认知功能障碍与年龄有关。这些发现指向了长期的 增强的海马区WNK1信号在胰岛素抵抗状态认知恶化发病机制中的作用 和衰老。我将在这份提案中检验这些假设。为此，我将接受胰岛素信号方面的重要培训 路径、神经科学、行为生理学和神经病理学在本提案的K99阶段 补充我之前在代谢病理生理学、生物化学、WNK1/OSR1激酶生物学、细胞 和分子生物学。我将得到一位胰岛素信号方面的领导者的指导--梅勒妮·科布博士，神经框架 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·胡伯博士， 突触运输--Ege T.Kavalali博士，衰老与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，以及整体科学训练环境 UTSW的世界级研究机构。在胰岛素和WNK1/OSR1信号方面建立独特的技能集 除了新陈代谢、神经科学、行为生理学和神经病理生理学之外， 支持我过渡到独立研究的学术职位，并将导致分子的发现 阿尔茨海默病等疾病中与年龄相关的认知损害中潜在的神经代谢障碍的介体。

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 My unpublished preliminary data highly suggest upregulated hippocampal WNK/OSR1 in cognitive deterioration via inhibition of insulin/AKT signaling, OSR1/sortilin- dependent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.