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.

抽象的该提案旨在为我检查 WNK1/OSR1 信号传导的长期职业计划提供重要的培训导致年龄相关认知发病机制的神经元代谢改变的机制阿尔茨海默病 (AD) 是导致痴呆的主要原因。动物模型的新研究表明，进行性认知能力下降和神经精神症状。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，调节认知并促进 AD 等疾病的发病机制然而，确切的分子介质。调节海马胰岛素信号介导的葡萄糖摄取及其在认知过程中的作用仍有待完全阐明，我建议研究蛋白激酶 WNK1/OSR1 在中的贡献。海马胰岛素信号传导、分拣蛋白介导的葡萄糖转运蛋白 4 (GLUT4) 依赖性葡萄糖摄取和虽然无赖氨酸 (K) 1 (WNK1) 及其底物氧化应激反应 1。 (OSR1) 与多种表现出认知和精神障碍的疾病有关，我未发表的初步数据强烈表明所涉及的机制细节尚不清楚。海马 WNK/OSR1 通过抑制胰岛素/AKT 信号、OSR1/sortilin 导致认知恶化我的数据还表明 WNK1-AKT 串扰和葡萄糖摄取呈负相关。这种复杂控制的 WNK1-AKT 轴的破坏使小鼠容易出现代谢功能障碍，这是抑制 WNK1 下游信号传导也可逆转胰岛素/AKT 信号传导。这些发现表明，胰岛素抵抗状态下的认知功能障碍是长期存在的。胰岛素抵抗状态认知恶化发病机制中海马 WNK1 信号增强我将在本提案中测试这些假设，为此，我将接受胰岛素信号传导方面的重要培训。该提案的 K99 阶段期间的通路、神经科学、行为生理学和神经病理学补充我之前在代谢病理生理学、生物化学、WNK1/OSR1 激酶生物学、细胞方面的培训我将得到胰岛素信号传导领域的领导者 Melanie Cobb 博士（神经框架）的指导。基础代谢和行为 - Jeffrey Zigman 博士，记忆的分子基础 - Kimberly Huber 博士，突触运输 - Ege T. Kavalali 博士，衰老和 AD 发病机制 - Ilya Bezprozvanny 博士。该提案利用了 Peter O’Donnell Jr. 脑研究所神经科学系的承诺，药理系、小鼠行为核心设施以及整体科学训练环境 UTSW 的世界一流研究机构，在胰岛素和 WNK1/OSR1 信号传导方面建立了独特的技能。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，还将支持我过渡到独立研究学术职位，并将导致分子的发现 AD 等疾病中与年龄相关的认知障碍中潜在神经元代谢破坏的介质。