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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

抽象的该建议旨在为我的长期职业计划提供关键培训，以检查WNK1/OSR1信号传导导致与年龄相关的认知发病机理的基础神经元代谢改变的机制痴呆症的损害。阿尔茨海默氏病（AD）是与年龄有关的主要原因，其特征是通过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会破坏海马神经元的胰岛素信号传导和葡萄糖利用调节认知并有助于诸如AD之类的疾病的发病机理。但是，确切的分子介质调节海马及其在认知过程中的作用，调节胰岛素信号传导介导的葡萄糖摄取保持充分阐明。我建议研究蛋白激酶WNK1/OSR1在海马胰岛素信号传导，Tortilin介导的葡萄糖转运蛋白4（GLUT4）依赖性葡萄糖摄取和认知功能。虽然没有赖氨酸（K）1（WNK1）及其底物氧化应激响应1 （OSR1）与表现出认知和精神障碍的多种疾病有关涉及的机械细节尚不清楚。我未发表的初步数据强烈建议更新海马WNK/OSR1通过抑制胰岛素/AKT信号传导，OSR1/Tortilin-- 依赖的GLUT4运输和葡萄糖吸收。我的数据还表明WNK1-AKT串扰和负面这种复杂控制的WNK1-AKT轴的破坏使小鼠易于代谢功能障碍，这是抑制WNK1下游信号传导后反转。胰岛素/AKT信号的破坏也是基础胰岛素抵抗状态的认知功能障碍以年龄的依赖方式。这些发现指向长期增强的海马WNK1信号传导在胰岛素耐药性状态的认知确定发病机理中和老化。我将在此提案中检验这些假设。为此，我将获得胰岛素信号传导的关键培训该提案的K99阶段期间的途径，神经科学，行为生理和神经病理学补充我以前在代谢病理生理学，生物化学，WNK1/OSR1激酶生物学，细胞的培训和分子生物学。我将由胰岛素信号的领导者打电话给我 - 梅兰妮·科布博士，神经框架潜在的新陈代谢和行为 - 记忆的分子基础Jeffrey Zigman博士 - 金伯利·胡伯博士，突触运输 - Ege T. Kavalali博士，AD发病机理的衰老和机制-Ilya Bezprozvanny博士。该提议利用了彼得·奥·唐纳尔小脑研究所的承诺，神经科学系药理学系，老鼠行为核心设施和整体科学培训环境 UTSW的世界一流研究机构。在胰岛素和WNK1/OSR1信号传导中建立独特的技能除了代谢，神经科学，行为生理和神经病理生理学外，途径还将支持我向独立研究学术职位的过渡，并将导致发现分子 AD等疾病中与年龄相关的认知障碍中神经元代谢中的介体的基础。