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.

Public Health Relevance

Age-related macular degeneration (AMD) is the most common cause of legal blindness in the elderly population in the United States and other developed countries. However, there are no treatments for the dry form of AMD because the causes of the disease are not well understood. Recent research suggests that hydroquinone, an environmental toxicant present in cigarette smoke, air pollutants, and plastics, is a potential cause of dry AMD. The goals of this project are to develop a novel mouse model to study dry AMD, to understand how hydroquinone might cause dry AMD through its effects on the mitochondria (the ?energy generator? of the cell) in the retinal pigment epithelium (the ?nurse cell layer? that supports the retina), to determine whether mitochondrial dysfunction may also play a role in established mouse models of dry AMD, and to determine whether mitochondrial dysfunction might be a therapeutic target in dry AMD.

National Institute of Health (NIH)
National Eye Institute (NEI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Shen, Grace L
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Duke University
Schools of Medicine
United States
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