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

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 My unpublished preliminary data highly suggest upregulated hippocampal WNK/OSR1 in cognitive deterioration via inhibition of insulin/AKT signaling, OSR1/sortilin- dependent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