Project Grant F31DK146671

DIURETIC HORMONE 44 (DH44) ORCHESTRATES METABOLIC HOMEOSTASIS IN DROSOPHILA MELANOGASTER - PROJECT SUMMARY METABOLIC HOMEOSTASIS IS MAINTAINED BY ACTIVE MODULATION OF PHYSIOLOGY AND BEHAVIOR. NEUROPEPTIDES ARE SIGNALING MOLECULES THAT DIRECTLY IMPACT AVAILABLE ENERGY RESERVES BY COORDINATING RESPONSES TO STRESS AND CHANGES IN INTERNAL STATES. DYSREGULATION OF NEUROPEPTIDE SIGNALING UNDERLIES METABOLIC DISEASES INCLUDING DIABETES AND OBESITY. PREVIOUS WORK IN DROSOPHILA MELANOGASTER DEMONSTRATED THE IMPORTANCE OF INSULIN- PRODUCING CELLS (IPCS) AND ADIPOKINETIC-HORMONE PRODUCING CELLS (APCS) IN MAINTAINING METABOLIC HOMEOSTASIS, AKIN TO THE ACTION OF MAMMALIAN INSULIN AND GLUCAGON. IPCS AND APCS ARE KNOWN TO RESPOND TO CHANGES IN CIRCULATING NUTRIENT LEVELS, HOWEVER, THESE CELL-TYPES ARE NOT CAPABLE OF DIRECTLY SENSING CARBOHYDRATES OR LIPIDS. EMERGING WORK SUGGESTS THAT DIURETIC HORMONE 44 (DH44) PRODUCING NEURONS IN DROSOPHILA ARE NUTRIENT-SENSING, PLAYING A CENTRAL ROLE IN METABOLISM BY INTEGRATING NUTRIENT SIGNALS, HORMONAL RELEASE, AND FEEDING BEHAVIOR. IMPORTANTLY, PRELIMINARY DATA INDICATES THE PRESENCE OF DH44 RECEPTORS IN IPCS, APCS, AND THE METABOLICALLY ACTIVE FAT BODY (LIVER-ADIPOSE EQUIVALENT). HOWEVER, THE METABOLIC PHYSIOLOGY AND BEHAVIORS MODULATED BY DH44 SIGNALING TO THESE TARGETS IN NORMAL AND DISEASE STATES IS UNKNOWN. THE OBJECTIVE OF THE RESEARCH PROGRAM OUTLINED IN THIS PROPOSAL IS TO ELUCIDATE THE ROLE OF DH44 NEUROPEPTIDE IN WHOLE-BODY METABOLIC HOMEOSTASIS AND FEEDING BEHAVIORS IN DROSOPHILA. MY CENTRAL HYPOTHESIS IS THAT DH44 ORCHESTRATES METABOLIC HOMEOSTASIS BY ACTING ON IPCS, APCS, AND THE FAT BODY, AND IS REQUIRED FOR THE DEVELOPMENT OF OBESITY/DIABETES-LIKE PHENOTYPES. TO CHARACTERIZE THE ROLE OF DH44 IN METABOLIC HOMEOSTASIS AND FEEDING BEHAVIORS IN DROSOPHILA, AIM 1 WILL INVESTIGATE THE CONTEXTS UNDER WHICH DH44 SIGNALING TO THE FLY FAT BODY, APCS, AND IPCS IS INCREASED USING A NOVEL GENETIC SENSOR. ADDITIONALLY, I WILL DETERMINE THE SIGNALING CONSEQUENCES OF DH44 TO IPCS, APCS, AND THE FAT BODY USING DH44 RECEPTOR KNOCKDOWNS IN THESE TARGETS. AIM 2 WILL DETERMINE THE ROLE OF DH44 IN THE PATHOGENESIS OF DIABETES AND OBESITY BY USING A HIGH SUGAR DIET (HSD) REGIMEN TO INDUCE DYSFUNCTIONAL METABOLISM. THE ROLE OF DH44 IN HSD-INDUCED DIABETES AND OBESITY WILL BE TESTED BY GENETICALLY REDUCING DH44 SIGNALING. THIS INTERDISCIPLINARY RESEARCH PROJECT AND TRAINING IN THE FIELDS OF NEUROSCIENCE, METABOLISM, AND ENDOCRINOLOGY HAS DIRECT APPLICATIONS TO MECHANISMS IN HUMAN METABOLIC DISEASE. THIS 2-YEAR PREDOCTORAL TRAINING AT THE UNIVERSITY OF NEVADA, RENO (UNR) WILL CONSIST OF RESEARCH, PROFESSIONAL AND CAREER DEVELOPMENT MENTORSHIP, AND NETWORKING. RESEARCH SUPPORT AND RESOURCES AT UNR ARE EXCELLENT, INCLUDING THE INTEGRATIVE NEUROSCIENCE CENTER COBRE. TOGETHER, THE TRAINING PLAN AND INSTITUTIONAL ENVIRONMENT WILL PROVIDE THE NECESSARY TRAINING REQUIRED FOR THE CANDIDATE'S LONG-TERM GOAL OF BECOMING AN ACADEMIC PRINCIPAL INVESTIGATOR. ULTIMATELY, THE PROPOSED RESEARCH WILL CONTRIBUTE TO THE UNDERSTANDING OF NEUROENDOCRINE PATHWAYS GOVERNING METABOLIC PHYSIOLOGY LEADING TO MORE EFFECTIVE TREATMENTS FOR COMPLEX METABOLIC DYSFUNCTION.