"Genetic defects in proteins involved in the transduction of light in photoreceptor cells of the retina lead to severe retinal degenerations and blindness. Mutations that primarily affect rod function lead to retinitis pigmentosas. These diseases affect 1 in 4000 individuals, initially causing night blindness. As the gradual loss of rods eventually compromises cone cell viability, they lead to blindness. Mutations that affect cone function lead to cone dystrophies (CDs) or macular degenerations. There is no current cure for these diseases. The applicant will establish a lab in which the main interests will be: 1) study intracellular signaling in rod and cone photoreceptor cells in response to light, by combining mouse genetics with morphological, biochemical and electrophysiological analysis; and 2) use mouse models to study how genetic defects in these signaling pathways lead to retinal degeneration. In this frame, the first main aim of this proposal is to establish mouse models of the adCDs caused by mutations in the gene encoding Guanylate Cyclase Activating Protein 1 (GCAP1), a Ca2+-binding protein that regulates cGMP synthesis in rods and cones. By expressing mutant forms of the protein in murine rods, and subsequently in cones we will study the pathways leading to cell death in vivo. The second main aim is to study the mechanisms that govern arrestin intracellular localization in darkness and its massive redistribution in response to light. This is a defense mechanism of rod photoreceptors to adapt and to protect themselves to prolonged light exposures (e.g. during cone-operated vision), and its understanding will be relevant for the dark/light physiology or photoreceptor cells."