Use of systems pharmacology to prevent rod and cone photoreceptor degeneration

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ABSTRACT An interdisciplinary consortium of investigators from the Departments of Pharmacology and Ophthalmology at Case Western Reserve University, the Cleveland Louis Stokes VA Medical Center, the Cole Eye Institute at Cleveland Clinic Foundation, Washington University, Michigan State University, Johns Hopkins University and ingenious Targeting Laboratory, Inc., proposes "to increase the pace at which basic science discoveries of disease mechanisms can be translated into therapies for complex visual system disorders and disease", a goal of the R24 National Eye Institute Translational Research Program on Therapy for Visual Disorders. This scientific partnership will employ its diverse expertise to evaluate potential therapies for retinal diseases in animal models by using a cutting-edge systems pharmacology paradigm. By screening a combination of G protein-coupled receptor (GPCR) agonist/antagonist drugs (modulators) for their ability to prevent retinal pathology in animal models of various rod and cone photoreceptor cell retinopathies, we will identify suitable candidates for future testing in humans. High resolution imaging methods and transcriptional analysis among other approaches will be used to monitor the efficacy and safety of these combination therapies. The goals of this project are: Aim 1. Test in mice the efficacy of a combination of GPCR agonists/antagonists in protecting against light-induced retinal damage and with either spontaneous rapid or slowly-progressing cone degeneration. Aim 2. Pharmacologically and genetically validate the involvement and specificity of identified GPCRs and their precise subcellular localization using knockin mice with T4 lysosome (T4L) fused into their signaling domains and an antibody we developed against T4L. We also will use the FAST system that allows various genetic outcomes (from inactivation to overexpression) to be engineered in a single mouse model. Aim 3. Assess the effectiveness of GPCR therapy in a canine rod-cone retinopathy model. Aim 4. Expand the range of receptor modulators to include therapeutic antibodies. Fulfilling these interrelated aims will direct our development of more successful therapies for people with incurable blinding diseases.