Responses of the Macula to Toxicant Injury: The Role(s) of PGC1α Isoforms in Photoreceptor Neuroprotection

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PROJECT SUMMARY The goal of this NIH Mentored Research Career Development Award application is to facilitate the transition of the candidate into an independent clinician-scientist. Her long-term career goal is to apply her skills in comparative ophthalmology and molecular genetics to develop novel treatments to address human blindness caused by the dry form of age-related macular degeneration (AMD), for which there is an unmet therapeutic need. Her short-term goal in this 4-year K08 program is to train in mechanisms of toxicant-induced pathology and modelling human exposures in animal models. She will capitalize on the unique environment in and around NC State University, including the NC State P30 funded Center for Human Health and the Environment and the close proximity of her laboratory to both Duke University and the National Institute for Environmental Health Sciences, where mentors and collaborators are located. Key elements of the career development plan include support from a diverse mentorship committee with expertise relating to all aspects of the proposal, spanning toxicology, mitochondrial biology, electroretinography and animal models of AMD. The candidate will participate in didactic training in toxicology, electron microscopy and electroretinography, present at meetings, publish her work, and ultimately, submit an R01 proposal to the National Eye Institute (NEI). The candidate’s research project integrates optimally with her career goals and training program. The project will determine the consequences of exposure of the cigarette smoke toxicant hydroquinone on mitochondrial density, morphology and function in macular photoreceptors and RPE, and will define the role(s) of different isoforms of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) on mitochondrial health in the retina. Novel animal models will be used that enable study of macular photoreceptors and PGC1α activity. The specific aims are: 1: To determine whether hydroquinone exposure impairs macular photoreceptor function and reduces PGC1α and mitochondrial density in a relevant animal model. 2: To determine whether deletion of specific Pgc1α isoforms leads to development of AMD – like disease in mice and whether this can be exacerbated by hydroquinone. This work is expected to yield important insights into why the macula suffers most from dry AMD. The mechanisms of macular susceptibility are poorly defined, and the study is therefore relevant to the mission of the NEI. The work will also lead to discovery of novel mediators of retinal mitochondrial health, which may be candidates as treatments for dry AMD.