WNK1/OSR1 AXIS IN HIPPOCAMPAL INSULIN SIGNALING, GLUCOSE METABOLISM AND AGE-RELATED COGNITIVE DYSFUNCTION -…

Assistance award details

Assistance award identifier

ASST_NON_R00AG075161_075

FAIN

R00AG075161

Recipient

THE UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$248,999

Period

Dec 1, 2022 – Mar 31, 2029

Fiscal year

2026

Place of performance state

TX

Source file

FY2026_All_Assistance_Full_20261006.zip

Description

WNK1/OSR1 AXIS IN HIPPOCAMPAL INSULIN SIGNALING, GLUCOSE METABOLISM AND AGE-RELATED COGNITIVE DYSFUNCTION - 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 MY UNPUBLISHED PRELIMINARY DATA HIGHLY SUGGEST UPREGULATED HIPPOCAMPAL WNK/OSR1 IN COGNITIVE DETERIORATION VIA INHIBITION OF INSULIN/AKT SIGNALING, OSR1/SORTILIN- DEPENDENT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 PATHOGENES