Various congenital retinal disorders are ?phototransduction diseases?, caused by abnormalities in photoreceptor signaling mechanisms mediated by cyclic cGMP (cGMP). One of the fundamentals in photoreceptor signaling and physiology is cGMP synthesis catalyzed by retinal guanylyl (guanylate) cyclase (RetGC), controlled by calcium, guanylyl cyclase activating proteins (GCAPs), and retinal degeneration 3 (RD3) protein. Defects in RetGC activity and/or regulation cause severe forms of congenital blindness ? Leber congenital amaurosis 1 (LCA1) and dominant cone-rod dystrophy 6 (CORD6). The high importance and the basic principles of the RetGC regulation in photoreceptor signaling and survival have been established, yet some key mechanistic aspects remain insufficiently understood. That includes those protein interactions of RetGC that define its biological function and, when affected, trigger retinal diseases. This proposal, conforming to the NEI mission to support research with respect to blinding eye diseases, visual disorders and mechanisms of visual function, is build on recent new advancements in studying RetGC regulation in photoreceptor physiology and disease: 1) identification of protein determinants critical for RetGC interactions with GCAPs and RD3; 2) location of RetGC binding domain on RD3; 3) development of a first mouse genetic model for studying CORD6 degeneration caused by mutation in RetGC1; 4) advancements in RetGC1 gene delivery mediated by adeno-associated viral (AAV) vectors; and 5) delineating multiple physiological consequences of mutations in different structural domains of RetGC1 causing LCA1 and CORD6. We here propose a broad study to evaluate new hypotheses and provide in-depth mechanistic understanding of regulatory processes in cGMP synthesis, by integrating protein biochemistry, molecular biology, molecular genetics and gene delivery.
Aim 1 will address the molecular mechanisms underlying RetGC regulation by GCAPs and RD3.
Aim 2 will determine how a RetGC1 mutation linked to CORD6 triggers photoreceptor death using a newly developed transgenic mouse model of CORD6 degeneration.
Aim 3 will seek better understanding of molecular and cellular mechanisms controlled by RD3 in regulation of the RetGC activity. By completing these specific aims, we expect to reach a deeper and more reliable understanding of how RetGC function and regulation define its role in normal photoreceptor physiology and in congenital diseases of the retina.
Mutations affecting cGMP synthesis in photoreceptors cause severe congenital blindness ? cone and rod dystrophies and Leber's congenital amaurosis. In this application, we seek a deeper understanding of the molecular mechanisms underlying regulation of cGMP synthesis in rod and cone function and expect that this new knowledge will help better understand the origin of the diseases and design strategies for their treatment.
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