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      A systems biology approach towards understanding and treating non-neovascular age-related macular degeneration

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          Abstract

          Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly in the developed world. While treatment is effective for the neovascular or “wet” form of AMD, no therapy is successful for the non-neovascular or “dry” form. Here we discuss the current knowledge on dry AMD pathobiology and propose future research directions that would expedite the development of new treatments. In our view, these should emphasize system biology approaches that integrate omic, pharmacological, and clinical data into mathematical models that can predict disease onset and progression, identify biomarkers, establish disease causing mechanisms, and monitor response to therapy.

          Abstract

          No effective therapies exist for dry age-related macular degeneration. In this perspective, the authors propose that research should emphasize system biology approaches that integrate various ‘omics’ data into mathematical models to establish pathogenic mechanisms on which to design novel treatments, and identify biomarkers that predict disease progression and therapeutic response.

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          Most cited references94

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          A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss

          (2001)
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            Oxidative damage-induced inflammation initiates age-related macular degeneration.

            Oxidative damage and inflammation are postulated to be involved in age-related macular degeneration (AMD). However, the molecular signal(s) linking oxidation to inflammation in this late-onset disease is unknown. Here we describe AMD-like lesions in mice after immunization with mouse serum albumin adducted with carboxyethylpyrrole, a unique oxidation fragment of docosahexaenoic acid that has previously been found adducting proteins in drusen from AMD donor eye tissues and in plasma samples from individuals with AMD. Immunized mice develop antibodies to this hapten, fix complement component-3 in Bruch's membrane, accumulate drusen below the retinal pigment epithelium during aging, and develop lesions in the retinal pigment epithelium mimicking geographic atrophy, the blinding end-stage condition characteristic of the dry form of AMD. We hypothesize that these mice are sensitized to the generation of carboxyethylpyrrole adducts in the outer retina, where docosahexaenoic acid is abundant and conditions for oxidative damage are permissive. This new model provides a platform for dissecting the molecular pathology of oxidative damage in the outer retina and the immune response contributing to AMD.
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              Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration on OCT: Classification of Atrophy Report 3.

              To develop consensus terminology and criteria for defining atrophy based on OCT findings in the setting of age-related macular degeneration (AMD).
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                Author and article information

                Contributors
                jthanda@jhmi.edu
                farrer@bu.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                26 July 2019
                26 July 2019
                2019
                : 10
                : 3347
                Affiliations
                [1 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Wilmer Eye Institute, , Johns Hopkins University, ; Baltimore, 21287 MD USA
                [2 ]ISNI 0000000100241216, GRID grid.189509.c, Department of Ophthalmology, , Duke University Medical Center, ; Durham, 27708 NC USA
                [3 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, Translational Health Sciences (Ophthalmology), , University of Bristol, ; Bristol, BS8 1TH UK
                [4 ]ISNI 0000000121901201, GRID grid.83440.3b, University College London, Institute of Ophthalmology and the National Institute for Health Research Biomedical Research Centre, , Moorfields Eye Hospital and UCL-Institute of Ophthalmology, ; London, WC1E 6BT UK
                [5 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Department of Ophthalmology, Jules Stein Eye Institute, David Geffen School of Medicine, , UCLA, ; Los Angeles, 90095 CA USA
                [6 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Brain Research Institute, , UCLA, ; Los Angeles, 90095 CA USA
                [7 ]ISNI 000000041936754X, GRID grid.38142.3c, Retina Service, Massachusetts Eye and Ear, Harvard Ophthalmology AMD Center of Excellence, Department of Ophthalmology, , Harvard Medical School, ; Boston, 02114 MA USA
                [8 ]ISNI 0000 0001 2190 1447, GRID grid.10392.39, Department of Ophthalmology, Institute for Ophthalmic Research, , University of Tübingen, ; Tübingen, D-72076 Germany
                [9 ]ISNI 0000 0004 1936 8796, GRID grid.430387.b, Institute of Ophthalmology and Visual Science, New Jersey Medical School, , Rutgers University, ; Newark, 07103 NJ USA
                [10 ]ISNI 0000 0004 1936 7558, GRID grid.189504.1, Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Epidemiology, and Biostatistics, , Boston University Schools of Medicine and Public Health, ; Boston, 02118 MA USA
                Author information
                http://orcid.org/0000-0001-9498-7982
                http://orcid.org/0000-0003-2046-3996
                Article
                11262
                10.1038/s41467-019-11262-1
                6659646
                31350409
                aae8ca8a-995c-4461-b360-992556f243be
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 31 July 2018
                : 3 July 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/100006312, BrightFocus Foundation (BrightFocus);
                Funded by: FundRef https://doi.org/10.13039/100007732, American Macular Degeneration Foundation (AMDF);
                Funded by: FundRef https://doi.org/10.13039/100001818, Research to Prevent Blindness (RPB);
                Award ID: Catalyst Award
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);
                Award ID: EY027691
                Award Recipient :
                Funded by: Wilmer-Bayer Alliance Grant, Bayer Pharmaceuticals, Inc
                Funded by: FundRef https://doi.org/10.13039/100001694, International Retinal Research Foundation (International Retinal Research Foundation, Inc.);
                Funded by: FundRef https://doi.org/10.13039/501100000833, Rosetrees Trust;
                Funded by: FundRef https://doi.org/10.13039/100010661, EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020);
                Categories
                Perspective
                Custom metadata
                © The Author(s) 2019

                Uncategorized
                biomarkers,visual system,macular degeneration,systems biology
                Uncategorized
                biomarkers, visual system, macular degeneration, systems biology

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