Clark Lab

Molecular mechanisms driving age-related macular degeneration

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2023

  1. Bucher K, Rodriguez-Bocanegra E, Wissinger B, Strasser T, Clark SJ, Birkenfeld AL, Siegel-Axel D and Fischer MD. (2023). Extra-viral DNA in adeno-associated viral vector preparations induces TLR9-dependent innate immune responses in human plasmacytoid dendritic cells. Sci. Reps. 1890. https://doi.org/10.1038/s41598-023-28830-7
  2. de Jong S, Tang J, and Clark SJ (2023) Age-related macular degeneration: A disease of extracellular complement amplification. Immun. Reviews 313, 279 DOI: https://doi.org/10.1111/imr.13145

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2022

  1. Merle, D.A., Sen, M., Armento, A., Stanton, C.M., Thee, E.F., Meester-Smoor, M.A., Kaiser, M., Clark,S.J., Klaver, C.W., Keane, P.A., Wright, A.F., Ehrmann, M. and Ueffing, M. (2022) 10q26 – The enigma in age-related macular degeneration. Prog. Retin. Eye Res. Early online release https://doi.org/10.1016/j.preteyeres.2022.101154

  2. Tierney AL, Alali WM, Scott T, Rees-Unwin KS, CITIID-NIHR BioResource COVID-19 Collaboration, Clark SJ and Unwin RD (2022) Levels of soluble complement regulators predict severity of COVID-19 symptoms. Front. Immunol. 13, 1032331. DOI: https://doi.org/10.3389/fimmu.2022.1032331
  3. Mcharg, S., Booth, L., Perveen, R, Riba Garcia I., Brace, N., Bayatti, N., Sergounitis, P.I., Phillips A. M., Day, A.J., Black, G.C., Clark, S.J., Dowsey AW, Unwin R.D and Bishop, P.N. (2022) Mast cell infiltration of the choroid and protease release are early events in age-related macular degeneration associated with genetic risk at both chromosomes 1q32 and 10q26. Proc. Natl. Acad. Sci. USA, 119, e2118510119. https://doi.org/10.1073/pnas.2118510119
  4. Unwin, R., Couto, D, and Clark, S.J. (2022) Theranos’s lesson for investors: speak to lab workers. Nature 601, 508. DOI: https://doi.org/10.1038/d41586-022-00167-7

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2021

  1. Armento, A., Murali, A., Marzi, J., Almansa-Garcia, A.C., Arango-Gonzalez, B., Kilger, E., Clark, S.J., Schenke-Layland, K., Ramlogan-Steel, C.A., Steel, J.C. and Ueffing M. (2021) Complement Factor H Loss in RPE Cells Causes Retinal Degeneration in a Human RPE-Porcine Retinal Explant Co-Culture Model. Biomolecules, 11, 1621. DOI: 10.3390/biom11111621
  2. Merle, D., Provenzano, F., Ali Jarboui, M., Kilger, E., Clark, S.J., Deleidi, M., Armento, A. And Ueffing, M. (2021) mTOR Inhibition via Rapamycin Treatment Partially Reverts the Deficit in Energy Metabolism Caused by FH Loss in RPE Cells. Antioxidants, 10, 1944. DOI: 10.3390/antiox10121944
  3. Lijie Zhai, L., Bell, A., Ladomersky, E., Lauing, K.L., Bollu, L., Nuygen, B., Genet, M., Kim, M., Chen, P., Mi, X., Kocherginski, M., Wu, J.D., Schipma, M.J., Wray, B., Griffiths, J., Unwin, R., Clark, S.J., Acharya, R., Bao, R., Horbinski, C., Lukas, R.V., Schiltz, G.E. and Wainwright, D.A. (2021) Tumor cell IDO enhances immunesuppression and decreases survival independent of tryptophan metabolism. Clin. Cancer Res. Accepted 25th Aug. https://doi.org/10.1158/1078-0432.CCR-21-1392
  4. Armento, A., Schmidt, TL., Sonntag, I., Merle, D., Jarboui, MA., Kilger, E., Clark, SJ. and Ueffing, M. (2021) CFH loss in human RPE cells leads to inflammation and complement system dysregulation via the NF-ƙB pathway. Int. J. Mol. Sci. 22, 2727. https://doi.org/10.3390/ijms22168727
  5. Choudhury, R., Bayatti, N., Scharff, R., Szula, E, Tilakaratna, V., Udsen, M.S., McHarg, S., Askari, J.A., Humphries, M.J., Bishop, P.N. and Clark, S.J. (2021) FHL-1 interacts with human RPE cells through the a5b1 integrin and confers protection against oxidative stress. Sci. Rep. 11, 14175. https://doi.org/10.1038/s41598-021-93708-5
  6. Cipriani, V., Tierney, A., Griffiths, J.R., Sergouniotis, P.I., Zuber, V., Yates, J.R.W., Moore, A.T., Bishop, P.N., Clark, S.J.* and Unwin, R.D.* (2021) Beyond Factor H: the influence of genetic variation with age-related macular degeneration on circulating Factor H-like 1 and Factor H-related protein levels. Am. J. Hum. Genet. 108, 1-16.  https://doi.org/10.1016/j.ajhg.2021.05.015 
  7. Lorés-Motta, L., van Beek, A.E., Willems, E., Zandstra, J., Einhouse, A., Mary, J.L., Stucki, C., Bakker, B., IAMDG Consortium, Hoyng, C.B., Fauser, S., Clark S.J., de Jonge, M.I., Nogoceke, E., Koertvely, E., Jongerius, I., Kuijpers, T.W. and den Hollander, A.I. (2021) Factor H-related proteins in age-related macular degeneration. Am. J. Hum. Genet. 108, 1-18.  https://doi.org/10.1016/j.ajhg.2021.06.002 
  8. Armento, A., Ueffing, M. and Clark S.J. (2021) The complement system and age-related macular degeneration Cell. Mol. Life Sci. 1-19.  https://doi.org/10.1007/s00018-021-03796-9 

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2020

  1. Stravalaci, M., Davi, F., Parente, R., Gobbi, M., Bottazzi, B., Mantovani, A., Day, A.J., Clark, S.J., Romano, M.R. and Inforzato, A. (2020) Control of complement activation by the long pentraxin PTX3: implications in age-related macular degeneration. Accepted 28th Oct. Front. Pharmacol.
  2. Heesterbeek, T.J., Rouhi-Parkouhi, M., Church, S.J., Lechanteur, Y.T., Lorés-Motta, L., Kouvatsos, N., Clark, S.J., Bishop, P.N., Hoyng, C.B., den Hollander, A.I., Unwin, R.D. and Day, A.J. (2020) Barium and Cadmium plasma levels are elevated in patients with neovascular age-related macular degeneration, while Chromium plasma levels are decreased. Accepted 20th Oct. Exp. Eye Res.
  3. Armento, A., Honisch, S., Panagiotakopoulou, V., Sonntag, I., Jacob, A., Kilger, E., Deleidi, M. Clark, S.J. and Ueffing, M. Loss of complement factor H impairs antioxidant capacity and energy metabolism of human RPE cells. Sci. Rep. accepted May 2020
  4. Randles, M.J., Lausecker, F., Humphries, J.D., Byron, A., Clark, S.J., Miner, J.H., Zent, R., Humphries, M.J. and Lennon, R. (2020) Basement membrane ligands initiate distinct signaling networks to direct cell shape. Matrix Biology  in press available online 6th March.
  5. Cipriani, V., Lores-Motta, L., He, F., Fathalla, D., Tilakaratna, V., McHarg, S., Bayatti, N., Acar, I.E., Hoyng, C.B., Fauser, S., Moore, A.T., Yates, J.R.W., International Age-related Macular Degeneration Genomics Consortium (IAMDGC), Morgan, B.P., de Jong, E.K., den Hollander, A.I., Bishop, P.N and Clark, S.J. (2020) Factor H-related protein 4 drives complement activation in age-related macular degeneration. Nat. Commun. 11, 778.

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2019

  1. Taylor, R.L., Poulter, J.A., Downes, S.M., McKibbin, M., Khan, K.N., Inglehearn, C.F., Webster, A., Hardcastle, A.J., Michaelides, M., Bishop, P.N., Clark, S.J. and Black, G.C. (2019) Deleterious mutations in the CFH gene affecting alternatively encoded Factor H-like 1 protein cause early onset macular degeneration. Ophthalmol. 126, 1410-1421.
  2. Porter, L.F., Saptarshi, N., Fang, Y., Rathi, S., den Hollander, A., de Jong, E., Clark, S.J., Bishop, P.N., Olsen, T.W., Liloglu, T., Chavali, V.R.M. and Paraoan, L. (2019) Whole genome methylation profiling of the retinal pigment epithelium of individuals with age-related macular degeneration reveals differential methylation patterns for SKI, GTF2H4, and TNXB genes. Clin. Epigenet. 11, 6.

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2018

  1. Swinkels, M., Zhang, J., Tilakaratna, V., Bishop, P.N., Black, G., Perveen, R., McHarg, S., Day, A.J. and Clark, S.J. (2018) C-reactive protein binding properties of factor H-like protein 1 differ from complement factor H: implications for inflammation in the eye. Sci. Rep. 8, 1643.

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2017

  1. Clark, S.J., McHarg, S., Tilakaratna, V. Brace, N, and Bishop, P.N. (2017) Bruch’s membrane permeability maintains two immunologically independent sites in the eye: implications for treating age-related macular degeneration. Front. Immunol. 8, 1778.
  2. Clark, S.J. and Bishop, P.N. (2017) The eye as a complement dysregulation hotspot. Semin. Immunopathol. 40, 65-74.
  3. Parente, R., Clark, S.J., Inforzato, A. and Day, A.J. (2017) Complement factor H in host defense and immune evasion. Cell. Mol. Life Sci. 74, 1605-1624.

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2016

  1. Jehs, T., Faber, C., Udsen, M.S., Jager, M.J., Clark, S.J. and Nissen, M.H. (2016) Induction of chemokine secretion and monocyte migration by choroidal melanocytes in response to pro-inflammatory cytokines. Invest. Ophthalmol. Vis. Sci. 57, 6568-6579.
  2. Langford-Smith, A., Tilakaratna, V., Lythgoe, P.R., Clark, S.J., Bishop, P.N. and Day, A.J. (2016) Age and smoking related changes in metal ion levels in human lens: Implications for cataract formation. PLoS One 11, e0147576-e0147576.
  3. Black, J.R.M. and Clark, S.J. (2016) Age-related macular degeneration: GWAS to translation. Genet. Med. 18, 283-289.

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2015

  1. McHarg, S., Brace, N., Bishop, P.N. and Clark, S.J. (2015) Enrichment of Bruch’s membrane from human donor eyes. J. Vis. Exp. 105, e53382.
  2. McHarg, S., Clark, S.J., Day, A.J. and Bishop, P.N. (2015) Age-related macular degeneration and the role of the complement system. Mol. Immunol. 67, 43-50.
  3. Langford-Smith, A., Day, A.J., Bishop, P.N. and Clark, S.J. (2015) Complementing the sugar code: role of GAGs and sialic acid in complement regulation. Front. Immunol. 6:25.
  4. Clark, S.J. and Bishop, P.N. (2015) Role of factor H and related proteins in regulating complement activation in the macula. J. Clin. Med. 4, 18-31.

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2014

  1. Clark, S.J., Schmidt, C.Q., White, A.M., Hakobyan, S., Morgan, B.P. and Bishop, P.N. (2014) Identification of factor H-like protein 1 as the predominant complement regulator on Bruch’s membrane: implications for age-related macular degeneration. J. Immunol. 193, 4962-4970.
  2. Schramm, E.C., Clark, S.J., Triebwasser, M.P., Raychaudhuri, S., Seddon, J. and Atkinson, J.P. (2014) Genetic variants in the complement system predisposing to age-related macular degeneration: a review. Mol. Immunol. 61, 118-125. 
  3. Keenan, T.D.L., Pickford, C.E., Holley, R.J., Clark S.J., Lin, W., Dowsey, A.W., Merry, C.L., Day, A.J. and Bishop, P.N. (2014) Age-dependent changes in heparan sulfate in human Bruch’s membrane: implications for age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 55, 5370-5379. 
  4. Langford-Smith, A., Keenan, T.D.L., Clark, S.J., Bishop, P.N. and Day, A.J. (2014) The role of complement in Age-related Macular Degeneration: heparan sulphate, a zip code for complement factor H? J. Innate Immun. 6, 1-10.

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2013

  1. Clark, S.J., Bishop, P.N. and Day, A.J. (2013) The proteoglycan glycomatrix: a sugar microenvironment essential for complement regulation. Front. Immun. 4, 412.
  2. Clark, S.J., Ridge, L.A., Hakobyan, S., Uhrin, D., Morgan, B.P., Lennon, R., Würzner R., Bishop, P.N. and Day A.J. (2013) The two heparin-binding domains in complement factor H show differential contributions to binding site recognition in human eyes and kidneys. J. Immunol. 190, 2049–2057.

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2012

  1. Keenan, T.D.L., Clark, S.J., Unwin, R., Ridge, L.A., Day, A.J. and Bishop, P.N. (2012) Mapping the differential distribution of proteoglycan core proteins in the adult human retina, choroid and sclera. Invest. Ophthalmol. Vis. Sci. 53, 7528–7538.

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2011

  1. Clark, S.J., Keenan, T.D.L., Fielder, H.L., Collinson, L.J., Holley, R.J., Merry, C.L., van Kuppevelt, T.H., Day, A.J. and Bishop, P.N. (2011) Mapping the differential distribution of glycosaminoglycans in the adult human retina, choroid and sclera. Invest. Ophthalmol. Vis. Sci. 52, 6511-6521.
  2. Day, A.J., Clark, S.J. and Bishop, P.N. (2011) Understanding the molecular basis of AMD and how the identification of new mechanisms may aid the development of novel therapies. Exp. Rev. Ophthalmol. 6, 123-128.

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2010

  1. Clark, S.J., Perveen, R., Hakobyan, S., Morgan, B.P., Sim, R.B., Bishop, P.N. and Day, A.J. (2010) Impaired binding of the AMD-associated complement factor H 402H allotype to Bruch’s membrane in human retina. J. Biol. Chem. 285, 30192-30202.
  2. Clark, S.J., Bishop, P.N. and Day, A.J. (2010) Complement factor H and age-related macular degeneration: the role of glycosaminoglycan recognition in disease pathology. Biochem. Soc. Trans. 38, 1342-1348.

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2009

  1. Marson, A., Robinson, D.E., Brookes, P.N., Mulloy, B., Wiles, M., Clark, S.J., Fielder, H.L., Collinson, L.J., Cain, S.A., Kielty, C.M., McArthur, S., Buttle, D.J., Short, R.D., Whittle, J.D. and Day, A.J. (2009) A sugar array for the investigation of glycosaminoglycan-protein interactions. Glycobiology 19, 1537-1546.
  2. Orth, D., Khan, A.B., Naim, A., Grif, K., Brockmeyer, J., Karch, H., Joannidis, M., Clark, S.J., Day, A.J., Fidanzi, S., Stoiber, H., Dierich, M.P., Zimmerhackl, L.B. and Würzner, R. (2009) Shiga Toxin Activates Complement and Binds Factor H: Evidence for an Active Role of Complement in Hemolytic Uremic Syndrome. J. Immunol. 182, 6394-6400.

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2007

  1. Prosser, B., Johnson, S., Roversi, P., Clark, S.J., Tarelli, E., Sim, R.B., Day, A.J. and Lea, S.M. (2007) Expression, purification, co-crystallization and preliminary crystallographic analysis of sucrose octasulphate/human complement regulator Factor H SCRs 6-8.  Acta. Cryst. F63, 480-483.
  2. Prosser, B., Johnson, S., Roversi, P., Herbert, A., Uhrich, D., Tyrrell, J., Clark, S.J., Terelli, E., Barlow, P., Sim, R.B., Day, A.J. and Lea, S.M. (2007) Towards a structural basis for complement factor H age-related macular degeneration. J. Exp. Med. 204, 2277-2283.
  3. Fernando, A.N., Furtado, P.B., Clark, S.J., Gilbert, H.E., Day, A.J., Sim, R.B. and Perkins, S.J. (2007) Associative and structural properties of the region of complement factor H encompassing the Tyr402His disease-related polymorphism and its interactions with heparin. J. Mol. Biol. 368, 564-581.
  4. Sjöberg, A.P., Trouw, L., Clark, S.J., Heinegård, D., Sim, R.B., Day, A.J. and Blom, A.M.  (2007) Differential interactions of the complement factor H variant associated with age-related macular degeneration with several of its ligands. J. Biol. Chem. 282, 10894-10900.

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2006

  1. Clark, S.J., Higman, V.A., Mulloy, B., Perkins, S.J., Lea, S.M., Sim, R.B. and Day, A.J.  (2006) H384 allotypic variant of factor H associated with age-related macular degeneration has different heparin-binding properties from the non-disease-associated form. J. Biol. Chem. 281, 24713-24720.

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2004

  1. Mahoney, D.J., Whittle, J.D., Milner, C.M., Clark, S.J., Mulloy, B., Buttle, D.J., Jones, G.C., Day, A.J., and Short, R.D. (2004) A method for the non-covalent immobilization of heparin to surfaces.  Anal. Biochem. 330, 123-129.

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