Project Grant R01DK138974

PARACRINE REGULATION OF ISLET CELL FUNCTION BY PRIMARY CILIA - PROJECT SUMMARY/ABSTRACT THE PRIMARY CILIUM PLAYS CRITICAL ROLES IN CELLULAR SIGNALING WHICH WITHIN THE PANCREATIC ISLETS ARE ESSENTIAL FOR THE PROPER REGULATION OF HORMONE SECRETION AND BLOOD GLUCOSE CONTROL. IN BOTH HUMANS AND RODENT MODELS, DIABETES MANIFESTS FROM MISREGULATED ISLET CELL SECRETORY FUNCTION DUE TO ALTERED CROSSTALK AND COORDINATION AMONG THE KEY ENDOCRINE CELLS, BUT THE ETIOLOGY OF ISLET CELL PARACRINE DYSREGULATION IN DIABETES IS UNKNOWN. OUR RECENT STUDIES REVEAL THAT PRIMARY CILIA ARE REQUIRED FOR THE MAINTENANCE OF ISLET FUNCTION BY ALLOWING ISLET CELLS TO SENSE AND RESPOND TO EACH OTHER'S ACTIVITY STATUS AS COMMUNICATED BY HORMONAL CUES. BASED ON THESE FINDINGS, WE HYPOTHESIZE THAT PRIMARY CILIA PROMOTE ISLET CELL COORDINATION BY MEDIATING PARACRINE HORMONE SIGNALING VIA THE MAJOR A- AND B-CELL HORMONES. TO THESE THIS HYPOTHESIS, WE WILL USE ISLET CELL- SPECIFIC PRIMARY CILIA DELETION MOUSE MODELS TO DELINEATE THE MECHANISMS BY WHICH A/B-CELL CILIA REGULATE PARACRINE HORMONE RELEASE AND ACTION ON TARGET CELLS. AIM 1 WILL DETERMINE WHETHER PRIMARY CILIA MEDIATE A-CELL INTRA-ISLET SIGNALING VIA GLUCAGON AND GLP-1. AIM 2 WILL DETERMINE WHETHER PRIMARY CILIA MEDIATE B-CELL INTRA-ISLET SIGNALING VIA INSULIN AND SEROTONIN. IN BOTH AIMS, WE WILL EMPLOY ORTHOGONAL IMAGING AND BIOCHEMICAL APPROACHES IN PRIMARY ISLETS TO DELINEATE A PHYSIOLOGIC ROLE FOR PRIMARY CILIA IN ISLET FUNCTION. A DETAILED UNDERSTANDING OF ISLET CELL INTER- REGULATION BY PRIMARY CILIA COULD SUPPORT THE DEVELOPMENT OF NOVEL THERAPIES TO TREAT OR PREVENT ISLET FAILURE IN DIABETES.