The mammalian visual system provides an excellent opportunity to understand how biological information processing systems operate in vivo and how they integrate with other cellular functions. Our long term goals are: (1) To understand the steps and biochemical mechanisms that operate in vivo to regulate and maintain the extraordinary performance characteristics of the phototransduction cascade in mammalian photoreceptors. (2) We want to understand how changes in the phototransduction circuit generate signals that induce cell death (apoptosis) and eventually retinal degeneration. A variety of age related, late onset retinal diseases are the result of apoptotic signaling and neural degeneration. Genetic modifications of components of the visual system provide models to study these effects and to evaluate gene therapy and pharmaceutical approaches designed to block apoptotic signaling in order to delay damage and prevent cell death in photoreceptors. In the next few years our laboratory will focus on developing multiple mutations and combinations of mutants and ectopic gene expression by breeding and by generating new genetic constructs designed to answer specific questions about the photocascade and about retinal degeneration. Some of our specific short term goals are: (1) To determine the nature of the factors that accelerate the GTPase activity of visual transducin. Is the RGS9 protein specifically involved in the rapid termination of the transducin mediated signal in vivo? Is RGS9 alone sufficient to account for this """"""""turn off""""""""? What is the nature of the molecular interactions of RGS with transducin? (2) To understand the molecular basis for rapid """"""""turn off"""""""" and reactivation that we observe in Rhodopsin Kinase deficient photoreceptors. (3) We will focus on the mechanisms that are required to generate light induced signals that lead to apoptosis, particularly in Rhodopsin Kinase and Arrestin deficient mice; (4) We will try to determine the in vivo role of other gene products involved in the dephosphorylation and the recycling of Rhodopsin during the photocascade and examine how they might be involved in inducing apoptosis; (5) We will continue to study the effects of deletion or overexpression of genes that are involved in apoptotic signaling or in blocking apoptosis under conditions that ordinarily lead to retinal degeneration.
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