Mitochondrial Dysfunction in a New Model of Dry AMD

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PROJECT SUMMARY Nonexudative, or “dry,” age-related macular degeneration (AMD) is a major cause of visual morbidity, for which there are no effective treatments. Our laboratory has previously implicated the environmental toxicant hydroquinone (HQ), which is found in cigarette smoke, pollutants, and plastics, as a potential cause of dry AMD. We have shown that aged mice fed a diet with low-dose HQ develop AMD-like sub-retinal pigment epithelium (RPE) deposits. Additionally, exposure of cultured RPE cells to HQ triggers numerous nonlethal injury responses (cytoskeletal disruption, cell “blebbing”, increased collagen synthesis, etc.) via activation of specific cytoplasmic signaling cascades (i.e. ASK1, p38 MAPK, pHSP25, others). Based on our preliminary studies, we propose the conceptual hypothesis that HQ and other AMD-relevant triggers promote subRPE deposit formation via induction of mitochondrial dysfunction. Linking in vitro observations of RPE cell culture to in vivo RPE biology has proven quite challenging because existing mouse models of subRPE deposits require aging, genetic manipulations, high-fat diet, or other injury (i.e. blue light, complement, etc.). Since these models are time-, cost-, and resource-intensive, they do not lend themselves to in-depth mechanistic studies to characterize the pathobiology of subRPE deposit formation. The purpose of this R21 proposal is to support exploratory studies of a novel mouse model for acute subRPE deposit formation, induced by subconjunctival exposure to HQ in young mice over a two-week period, (1) to show that these deposits are precursors of deposits in chronic models in aged mice; and (2) to characterize relevant biochemical mechanisms of deposit formation. Specifically, we seek to demonstrate the central role of mitochondrial dysfunction in triggering cytoplasmic signaling pathways that regulate subRPE deposit biology in vivo. Second, we desire to evaluate the ApoE4 lipid dysregulation model of subRPE deposits to assess biologic overlap between the ApoE4 deposit model and the acute periocular HQ model. Finally, this project will introduce a novel mitochondria-targeting peptide, MTP-131, to determine whether treatment of mitochondrial dysfunction can mitigate RPE cellular injury, and prevent and perhaps regress subRPE deposits. Positive findings in support of our conceptual hypothesis would validate mitochondrial dysfunction as a novel therapeutic target for dry AMD.