The goal of this project is to understand the roles of RGS proteins of the R7 subfamily in regulating the timing and sensitivity of intracellular signaling cascades in the vertebrate retina, and in influencing the course of retinal degeneration. RGS proteins are a family of Regulators of G Protein Signaling, the most common type of signaling pathway in the mammalian retina and throughout the body. G protein signaling pathways are the targets of most drugs. RGS proteins are uniquely poised to control the timing and amplitude of cellular responses to extracellular signals. Of particular importance in the retina and elsewhere in the central nervous system is the R7 subfamily. The critical role of one R7 subfamily member, RGS9-1, in determining the kinetics of photoresponse recovery in rod and cone photoreceptor cells is well established. There are four specific aims: 1. Structures and dynamics of complexes that carry out RGS protein function will be determined using multi-resolution biophysical techniques. 2. The role of RGS7 and its complexes in responses of ON bipolar to mGluR6 activation will be determined using biochemical and proteomic techniques along with collaborative electrophysiological approaches. 3. The role of RGS11 in retinal development and function will be explored using genetically engineered mice, immunolocalization, and proteomics. 4. The ability of increases in the concentration and activity of the RGS9-1-GP5-R9AP complex to prolong the survival of rods in retinal degenerative disorders will be tested. Understanding the roles of RGS proteins in G protein signaling is necessary to understand how these pathways, which serve as targets for most drugs, normally function, how they are disrupted in disease states and how they are impacted by therapies. Understanding the role RGS of proteins in vision will help us understand normal vision, and provide insight into retinal diseases and potential therapies. ? ? ?
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