Project Grant R03TR005223

CONDITIONAL KNOCK-IN OF GNB3/GNGT2 IN MOUSE ROD PHOTORECEPTORS - ABSTRACT. THE G-PROTEIN GB3 SUBUNIT ENCODED BY THE GENE GNB3, IS THE PROTEIN PRESENT IN MULTIPLE TISSUES AND CELL TYPES, INCLUDING RETINAL CONE PHOTORECEPTORS, AS PART OF THE GABG HETEROTRIMERS RESPONSIBLE FOR THE INTRACELLULAR SIGNALING INITIATED BY THE G-PROTEIN-COUPLED RECEPTORS, GPCRS. THERE IS EVIDENCE THAT MUTATIONS IN GNB3 ARE ASSOCIATED WITH CARDIOVASCULAR DISEASE, METABOLIC SYNDROME, OBESITY AND VISUAL IMPAIRMENT. RARE GNB3 MUTATIONS HAVE BEEN FOUND ASSOCIATED WITH RETINAL DEGENERATION AND CONGENITAL STATIONARY NIGHT BLINDNESS. THE MECHANISMS OF THESE PATHOPHYSIOLOGICAL CONDITIONS LINKED TO GNB3 ARE POORLY UNDERSTOOD. IN THE RETINA, THERE IS LITTLE UNDERSTANDING OF WHY MEMBERS OF THE SAME GENE FAMILY GNB3 AND GNB1 ARE EXPRESSED SELECTIVELY IN CONE AND ROD PHOTORECEPTORS, AND WHAT ROLES GB3 AND GB1, IN TIGHT COMPLEXES WITH THE CORRESPONDING GG SUBUNIT, GGC AND GG1, CONTRIBUTE TO THE DISTINCT PROPERTIES OF CONE AND ROD PHOTOTRANSDUCTION AND RETINAL DISEASES. THIS PILOT PROPOSAL FOCUSES ON THE INITIAL CHARACTERIZATION OF A UNIQUE MOUSE MODEL THAT OUR LABORATORY HAS DEVELOPED TO REPLACE THE ENTIRE ROD GB1G1 SUBUNIT COMPLEX WITH ITS CONE ANALOGUE GB3GC. THE PROPOSAL AIMS TO COLLECT CRITICAL PRELIMINARY DATA FOR A MORE COMPREHENSIVE PROJECT FOCUSING ON THE SPECIFICITY OF RETINAL SIGNALING AND MECHANISMS OF RETINAL DISORDERS INVOLVING GNB3. THIS PROJECT BUILDS THE NECESSARY FOUNDATION FOR FURTHER MECHANISTIC STUDIES OF SPECIFIC HUMAN MUTATIONS, AS WELL AS THE DEVELOPMENT OF NEW THERAPEUTIC APPROACHES.