Inner retinal dysfunction in retinitis pigmentosa

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Project Abstract Retinitis pigmentosa (RP) is the most common group of inherited retinal diseases (IRDs), leading to progressive photoreceptor degeneration and blindness. In addition to well-studied outer retinal dysfunction in RP, there is a growing body of rigorous work highlighting cellular adaptations in the inner retina, likely due to neural remodeling following deafferentation. The impact of this structural remodeling on the function of inner retina, and its consequences for visual function, are at present poorly understood. Electroretinography (ERG) provides a non-invasive method to assess inner retinal dysfunction both in the clinic and in animal models of retinitis pigmentosa, providing a means not only to provide insights into these questions, but also to translate mechanistic insights into potential therapeutic strategies for patients. The long term goal of the candidate is to become an independent clinician-scientist with the skills necessary to pursue strategies to prevent or restore vision loss in patients with IRDs. The scientific objective of the current proposal is to test the novel hypothesis, supported by preliminary data using a novel ERG protocol in both patients and animal models of retinal degeneration, that retinal remodeling leads to aberrant responses (noise) in inner retinal neurons that mask responses to a visual stimulus. The overarching goal of the proposal is to provide the candidate with the mentorship, skills, and support to realize a career dedicated to improve signal transmission in the degenerating retina. This is an essential area of research, as aberrant inner retinal responses limit the potential for functional improvement in all therapies that improve photoreceptor function. In Aim 1, the extent of inner-retina dysfunction will be assessed using novel ERG techniques in human subjects with RP. Aim 2 will develop ERG approaches to assess inner retinal remodeling in a mouse model of RP (the rd10 mouse model); Aim 3 will define the functional impact of photoreceptor degeneration in intracellular recordings of retinal ganglion cells in rd10 mice. This proposal describes a 4-year training program for developing an academic career focused on understanding retinal dysfunction in IRDs under an outstanding team of multidisciplinary mentors dedicated to the candidate’s objective of scientific independence. The proposal will leverage the candidate’s research training in neuroscience and clinical fellowship training in IRDs and vitreoretinal surgery under a mentorship team that has extensive experience in clinical retinal electrophysiology and psychophysics (Dr. Jason McAnany), animal electrophysiology and genetics (Dr. Neal Peachey), and single cell electrophysiology and imaging (Dr. Steve DeVries). Coursework and seminars will complement the mentorship team in the realization of ethical basic and translational research. The institutional environment in the Department of Ophthalmology & Visual Sciences at the University of Illinois-Chicago, with its corps of outstanding vision scientists and outstanding facilities, will maximize the candidate’s success in research and career development.