Ueffing Lab

Molecular Biology of Retinal Degenerations

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Age-related macular degeneration (AMD)

Age related-macular degeneration (AMD) is the leading cause of blindness in the elderly population. It is characterized by progressive degeneration of the macula, the central region of the retina. Here, the retinal pigment epithelium (RPE) cells become dysfunctional and thus can no longer support the retina, eventually leading to vision loss. AMD patients lose their central visual field, making it impossible to read, write, drive and recognize faces, which greatly impedes an independent and active life. So far, no therapy is available for the majority of AMD cases, mostly because suitable research models are lacking. AMD is a very complex disease, caused by an interplay of diverse risk factors (genetic predisposition, age and life-style factors), leading to changes in several molecular mechanisms and pathways.

Main Research Fields:

Genetic and lifestyle risks for AMD

The focus of our research lies in understanding AMD pathology driven by the two main genetic risk loci for AMD: the Complement System genes on Chomosome 1, particularly the Complement factor H (CFH) polymorphism Y402H, and the Chomosome10q26 locus, particularly HTRA1 and ARMS2 variants. Additional risk factors contributing to AMD are age and lifestyle factors, such as smoking or diet. A comprehensive analysis of these factors for AMD risk prediction has been carried out by the EU-funded EYE-RISK consortium (coordinator Prof. Ueffing).

AMD research models

Our goal is to build suitable AMD research models to better understand AMD pathology and to move forward in the discovery of potential therapeutic targets for AMD. AMD research models, besides accounting for the cell-cell interactions of the retina, have to reflect the complex interplay of the risk factors for AMD, including genetic risk and life-style habits, like diet or smoking. For this purpose, we have created a novel model comprising human RPE-cells in co-culture with porcine retinal explants, highly resembling the human macula. We use this newly established model to investigate the effect of several AMD risk factors on RPE cell function and on the neuroretina. It will also be used to test potential drugs to treat AMD. In addition, we are employing AMD patient-derived iPSC-RPE cells to investigate the influence of different genetic risks on RPE physiology.

Current Projects:

  • Impact of Complement Factor H Y402H polymorphism on RPE cells and AMD pathology. University of Tübingen ƒortüne-programme (2021 – 2023)
  • Elucidating the role of ARMS2 in extracellular matrix homeostasis and in choroidal neovascularization in AMD pathogenesis. Helmut-Ecker Foundation (2022-2024)

Collaborations:

  • Caroline Klaver, Erasmus Medical Center, Dept. of Ophthalmology and Epidemiology, Rotterdam, NL
  • Alan Wright, Chloe Stanton, The MRC Human Genetics Unit at the University of Edinburgh, UK
  • Berta De La Cerda Haynes, CABIMER (Andalusian Molecular Biology and Regenerative Medicine Centre), Sevilla, Spain
  • Michela Deleidi, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Tübingen, Germany
  • Katja Schenke-Layland, Julia Marzi, Natural and Medical Sciences Institute at the University of Tübingen (NMI) Reutlingen/Tübingen, Germany
  • Simon Clark, Institute for Ophthalmic Research, University of Tübingen, Germany
  • Philipp Berens, Institute for Ophthalmic Research, Werner Reichardt Centre for Integrative Neuroscience, University of Tübingen, Germany

Selected Publications:

  • Merle DA, Sen M, Armento A, Stanton CM, Thee EF, Meester-Smoor MA, Kaiser M, Clark SJ, Klaver CCW, Keane PA, Wright AF, Ehrmann M, Ueffing M. 10q26 - The enigma in age-related macular degeneration. Prog Retin Eye Res. 2022 Dec 10:101154.
  • Thee EF, Colijn JM, Cougnard-Grégoire A, Meester-Smoor MA, Verzijden T, Hoyng CB, Fauser S, Hense HW, Silva R, Creuzot-Garcher C, Ueffing M, Delcourt C, den Hollander AI, Klaver CCW. The phenotypic course of age-related macular degeneration for ARMS2/HTRA1: The EYE-RISK Consortium. Ophthalmology. 2022 Jul;129(7):752-764.
  • Merle DA, Provenzano F, Jarboui MA, Kilger E, Clark SJ, Deleidi M, Armento A. and Ueffing M.. mTOR inhibition via Rapamycin treatment partially reverts the deficit in energy metabolism caused by FH loss in RPE cells. Antioxidants. 2021.
  • Armento A, Murali A, Marzi J, Arango-Gonzalez B, Kilger E, Clark SJ, et al. FH loss in RPE cells causes retinal degeneration in a human RPE-porcine retinal explant co-culture model. Biomolecules. 2021;11(11):1621.
  • Armento A, Schmidt TL, Sonntag I, Merle D, Jarboui MA, Kilger E, et al. CFH loss in human RPE cells leads to inflammation and complement system dysregulation via the NF-κB pathway. IJMS 2021.
  • Armento A, Ueffing M, Clark SJ. The complement system in age-related macular degeneration. Cell Mol Life Sci. 2021;78(10):4487-505.
  • Colijn JM, Meester-Smoor M, Verzijden T, de Breuk A, Silva R, Merle BMJ, Cougnard-Grégoire A, Hoyng CB, Fauser S, Coolen A, Creuzot-Garcher C, Hense HW, Ueffing M, Delcourt C, den Hollander AI, Klaver CCW; EYE-RISK Consortium. Genetic Risk, Lifestyle, and Age-Related Macular Degeneration in Europe: The EYE-RISK Consortium. Ophthalmology. 2021 Jul;128(7):1039-1049.
  • Ajana S, Cougnard-Grégoire A, Colijn JM, Merle BMJ, Verzijden T, de Jong PTVM, Hofman A, Vingerling JR, Hejblum BP, Korobelnik JF, Meester-Smoor MA, Ueffing M, Jacqmin-Gadda H, Klaver CCW, Delcourt C; EYE-RISK Consortium. Predicting Progression to Advanced Age-Related Macular Degeneration from Clinical, Genetic, and Lifestyle Factors Using Machine Learning. Ophthalmology. 2021 Apr;128(4):587-597.
  • Armento A, Honisch S, Panagiotakopoulou V, Sonntag I, Jacob A, Bolz S, et al. Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells. Sci Rep. 2020;10(1):10320.
  • Handa JT, Bowes Rickman C, Dick AD, Gorin MB, Miller JW, Toth CA, Ueffing M, Zarbin M, Farrer LA. A systems biology approach towards understanding and treating non-neovascular age-related macular degeneration. Nat Commun. 2019 Jul 26;10(1):3347.
  • Kortvely E, Ueffing M. Common mechanisms for separate maculopathies? Adv Exp Med Biol. 2012;723:61-6.
  • Stanton CM, Yates JR, den Hollander AI, Seddon JM, Swaroop A, Stambolian D, Fauser S, Hoyng C, Yu Y, Atsuhiro K, Branham K, Othman M, Chen W, Kortvely E, Chalmers K, Hayward C, Moore AT, Dhillon B, Ueffing M, Wright AF. Complement factor D in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011 Nov 11;52(12):8828-34.
  • Kortvely E, Hauck SM, Duetsch G, Gloeckner CJ, Kremmer E, Alge-Priglinger CS, Deeg CA, Ueffing M. ARMS2 is a constituent of the extracellular matrix providing a link between familial and sporadic age-related macular degenerations. Invest Ophthalmol Vis Sci. 2010 Jan;51(1):79-88