Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. At present, no therapy will restore vision with any form of AMD. To address this shortcoming, this proposal will focus on mechanisms that could restore vision. The recycling of 11-cis-retinal (11-cRAL) by the visual cycle is an RPE function that is essential for vision. While oxidative stress and complement are integral factors in AMD pathophysiology, their impact on the visual cycle is undefined. The objective of this proposal is to define how oxidative stress and innate immunity impair the visual cycle to decrease vision in AMD. The hypothesis to be tested is that oxidative stress and impaired complement regulators Cfh and CD46 decrease the visual cycle network. The proposed specific aims are: 1. Determine the extent that oxidative stress i) impairs Cfh to induce inflammation which decreases visual cycle gene expression, and ii) induces Ptx3, and by regulating Cfh abundance, prevents visual cycle decline.
This aim will test the extent that decreased Cfh generates inflammation from increased complement or MDA mediated cytokine expression to activate Stat3, which decreases visual cycle gene expression, function, and vision, and the impact of Ptx3 on Cfh abundance to regulate Cfh mediated inflammation. 2. Determine the extent that chronic oxidative stress impairs the visual cycle through Notch signaling. Oxidative stress activates Notch signaling, which can induce the transcription factor Sox9 to control the expression of a network of 6 visual cycle genes. While acute Notch signaling increases Sox9, chronic Notch signaling decreases Sox9.
This aim will explore the extent that chronic oxidative stress activates Notch signaling, and how Notch influences visual cycle function through Sox9. 3. Determine the extent that CD46 regulates Notch signaling and Sox9 mediated visual cycle gene function. Besides its complement regulatory action, CD46 binds Jag1 to impede Notch signaling. Thus, decreased CD46 makes Jag1 available to activate Notch signaling as an alternative, non-complement function.
This aim will explore the extent that decreased CD46 influences Notch signaling and visual cycle function through Jag1. Since CD46 is not expressed in somatic rodent cells, we will use iPS RPE cells with mutations in key CD46 domains to address this aim. These contributions are significant because if successful, novel pathways will be identified as targets to treat vision loss in AMD. The research is innovative since we will investigate understudied areas including mechanisms of vision loss from the synergistic impact of oxidative stress and innate immunity, the role of Stat3, Notch, and Sox9, and unconventional, non-complement functions of complement regulators on the visual cycle using unique, state-of-the-art genetic mice with fresh, but decisive factors that have not been previously tested. Targeted therapy that neutralizes pathways that degrade visual cycle gene expression, function, and vision from oxidative stress and overactive innate immunity is expected to result from this work.

Public Health Relevance

Age-related macular degeneration (AMD), the most common cause of blindness among the elderly, is triggered by oxidative stress, which imbalances innate immunity. While vision can be 20/20, other aspects of vision are affected early in AMD where retinal pigment epithelial (RPE) cell visual cycle function, which is essential for vision, is impaired before the retina has overt injury. This proposal will study how oxidative stress damages the RPE, which impairs the visual cycle system to decrease vision in early AMD.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Mckie, George Ann
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Johns Hopkins University
Schools of Medicine
United States
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Ghosh, Sayan; Shang, Peng; Terasaki, Hiroto et al. (2018) A Role for ?A3/A1-Crystallin in Type 2 EMT of RPE Cells Occurring in Dry Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 59:AMD104-AMD113
Jun, Sujung; Datta, Sayantan; Wang, Lei et al. (2018) The impact of lipids, lipid oxidation, and inflammation on AMD, and the potential role of miRNAs on lipid metabolism in the RPE. Exp Eye Res :
Datta, Sayantan; Cano, Marisol; Ebrahimi, Katayoon et al. (2017) The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD. Prog Retin Eye Res 60:201-218