Project Grant R21DK137123

THE INWARD RECTIFIER POTASSIUM CHANNEL KIR7.1 IS AT THE CENTER OF ENERGY HOMEOSTASIS REGULATION - OBESITY IS A METABOLIC DISORDER OF PANDEMIC INCIDENCE IN DEVELOPING COUNTRIES AND THE UNITED STATES. THE DEVELOPMENT OF NEW THERAPEUTIC INTERVENTIONS TO HELP MITIGATE THIS DISEASE IS A SIGNIFICANT NEED IN THE CLINIC AND FOR PUBLIC HEALTH. GAINING INSIGHT INTO THE ROLE OF SPECIFIC BRAIN AREAS IN EATING BEHAVIOR WILL LEAD TO THE DISCOVERY OF TREATABLE TARGETS FOR WHICH DRUGS CAN BE DEVELOPED TO SUPPORT METABOLIC DISORDER TREATMENTS. IN SUPPORT OF THIS PROPOSAL, WE PRESENT NEW DATA SHOWING THAT CENTRAL AND PERIPHERAL ADMINISTRATION OF A SPECIFIC INWARD RECTIFIER POTASSIUM CHANNEL KIR7.1 BLOCKER, ML418, PRODUCES A ROBUST ANOREXIGENIC EFFECT. THESE RESULTS REVEAL A NEW TARGET IN THE SATIETY PATHWAY THAT HAS NOT BEEN PREVIOUSLY STUDIED. THE CURRENT APPLICATION IS CENTERED ON THE HYPOTHESIS THAT KIR7.1 REGULATES THE SENSITIVITY SETPOINT OF THE HYPOTHALAMIC NUCLEI INVOLVED IN ENERGY HEMOSTASIS. WE PROPOSE TO EMPLOY A TRAP (TARGETED RECOMBINATION IN ACTIVE POPULATIONS) APPROACH FOR ACCESSING AND CONTROLLING TARGET-SENSITIVE NEURAL CIRCUITRY THAT BECOMES ACTIVE AFTER THE PHARMACOLOGICAL INHIBITION OF KIR7.1 WITH ML418. THE FIRST AIM WILL IDENTIFY THE KIR7.1 RESPONSIVE NEURONS, AND IT WILL VALIDATE THE PARTICIPATION OF THESE NEURONS IN DETERMINING FEEDING BEHAVIORS BY CHALLENGING THE ACTIVATED CENTERS WITH A CHEMOGENETIC APPROACH. IN THE SECOND AIM, WE WILL IDENTIFY HYPOTHALAMIC CIRCUITRY ASSOCIATED WITH KIR7.1- ACTIVATED NEURONS THAT REGULATE ENERGY HOMEOSTASIS. THIS PROPOSAL PRESENTS KIR7.1 AS A NOVEL REGULATOR OF ENERGY HOMEOSTASIS AND A POTENTIAL TARGET FOR DEVELOPING NOVEL THERAPEUTIC APPROACHES AGAINST OBESITY. MORE GENERALLY, THIS WORK WILL ESTABLISH A FUNDAMENTAL PLATFORM FOR BASIC AND CLINICAL RESEARCH TO TREAT OBESITY AND EATING DISORDERS.