Institute for Ophthalmic Research

Head

Prof. Dr. rer. nat. Marius Ueffing

Institute Director

Email: marius [dot] ueffing [at] uni-tuebingen [dot] de

Contact

Division of Experimental Ophthalmology
Centre for Ophthalmology
Institute for Ophthalmic Research
Röntgenweg 11
72076 Tübingen        

Mission statement

Inherited retinal degenerations such as Retinitis Pigmentosa (RP)are a major cause of blindness in industrialized countries. In the division of experimental ophthalmology we are seeking to develop treatments for RP and related diseases that affect photoreceptors. We argue that neuroprotection or cell replacement as a survival- and function-upholding regime is a feasible approach to preserve functional vision in patients affected by inherited retinal degenerations.

We use different animal models for RP as well as retinal explant cultures to study signalling pathways that are involved in photoreceptor cell death or survival. Insights into these mechanisms are crucial for the successful development of potential therapies. Based on these, different neuroprotective strategies are evaluated for their capacity to prevent or delay photoreceptor cell death. Another approach to preserve vision is the replacement of diseased cells by transplantation of retinal progenitors that are induced to differentiate into functional photoreceptors and integrate into the pre-existing retinal networks.

In the course of our research we have established that treatment with a combination of the neurotrophic factors CNTF and BDNF partially rescues photoreceptors. Furthermore, we have identified several factors important for photoreceptor degeneration including calpain-type proteases and poly-ADP-ribose-polymerase (PARP).

A retinal explant in culture

 

 

 

 

 

 

 

Based on our findings on cell death mechanisms, we believe that neuroprotective treatments combined with a replacement of diseased cells constitutes the most promising approach to preserve and restore functional vision.

Staining for degenerating cells (TUNEL) on wild-type (wt) and retinal degeneration (rd1) retinal cross-sections at postnatal day 11.

 

 

 

Cross-sections through a wild-type (wt) and retinal degeneration (rd1) retina at postnatal day 30.

 

 

 

 

Selected publications

Griciuc A, Aron L, Ueffing M. "Looking into eyes: rhodopsin pathologies in Drosophila.", Adv Exp Med Biol. 2012;723:415-23. PubMed PMID: 22183360.

Kortvely E, Ueffing M. "Common mechanisms for separate maculopathies?", Adv Exp Med Biol. 2012;723:61-6. PubMed PMID: 22183316.

Kiel C, Vogt A, Campagna A, Chatr-aryamontri A, Swiatek-de Lange M, Beer M, Bolz S, Mack AF, Kinkl N, Cesareni G, Serrano L, Ueffing M. "Structural and functional protein network analyses predict novel signaling functions for rhodopsin.", Mol Syst Biol. 2011 Nov 22;7:551. doi: 10.1038/msb.2011.83. PubMed PMID: 22108793.

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. Print 2011. PubMed PMID: 22003108; PubMed Central PMCID: PMC3230905.

Van Campenhout CA, Eitelhuber A, Gloeckner CJ, Giallonardo P, Gegg M, Oller H, Grant SG, Krappmann D, Ueffing M, Lickert H. "Dlg3 trafficking and apical tight junction formation is regulated by nedd4 and nedd4-2 e3 ubiquitin ligases.", Dev Cell. 2011 Sep 13;21(3):479-91. PubMed PMID: 21920314.

Coene KL, Mans DA, Boldt K, Gloeckner CJ, van Reeuwijk J, Bolat E, Roosing S, Letteboer SJ, Peters TA, Cremers FP, Ueffing M, Roepman R. The ciliopathy-associated protein homologs RPGRIP1 and RPGRIP1L are linked to cilium integrity through interaction with Nek4 serine/threonine kinase.", Hum Mol Genet. 2011 Sep 15;20(18):3592-605. Epub 2011 Jun 17. PubMed PMID: 21685204.

Griciuc A, Aron L, Ueffing M. "ER stress in retinal degeneration: a target for rational therapy?", Trends Mol Med. 2011 Aug;17(8):442-51. Epub 2011 May 27. Review. PubMed PMID: 21620769.

Boldt K, Mans DA, Won J, van Reeuwijk J, Vogt A, Kinkl N, Letteboer SJ, Hicks WL, Hurd RE, Naggert JK, Texier Y, den Hollander AI, Koenekoop RK, Bennett J, Cremers FP, Gloeckner CJ, Nishina PM, Roepman R, Ueffing M. "Disruption of intraflagellar protein transport in photoreceptor cilia causes Leber congenital amaurosis in humans and mice.", J Clin Invest. 2011 Jun 1;121(6):2169-80. doi: 10.1172/JCI45627. Epub 2011 May 23. PubMed PMID: 21606596; PubMed Central PMCID: PMC3104757.

Webb KJ, Coolen M, Gloeckner CJ, Stigloher C, Bahn B, Topp S, Ueffing M, Bally-Cuif L. "The Enhancer of split transcription factor Her8a is a novel dimerisation partner for Her3 that controls anterior hindbrain neurogenesis in zebrafish.", BMC Dev Biol. 2011 May 17;11:27. PubMed PMID: 21586122; PubMed Central PMCID: PMC3125270.

Del Río P, Irmler M, Arango-González B, Favor J, Bobe C, Bartsch U, Vecino E, Beckers J, Hauck SM, Ueffing M. "GDNF-induced osteopontin from Müller glial cells promotes photoreceptor survival in the Pde6brd1 mouse model of retinal degeneration.", Glia. 2011 May;59(5):821-32. doi: 10.1002/glia.21155. Epub 2011 Feb 28. PubMed PMID: 21360756

Griciuc A, Aron L, Roux MJ, Klein R, Giangrande A, Ueffing M. (2010) "Inactivation of VCP/ter94 suppresses retinal pathology caused by misfolded rhodopsin in Drosophila.", PLoS Genet. Aug 26;6(8). pii: e1001075.

Kinzel D, Boldt K, Davis EE, Burtscher I, Trümbach D, Diplas B, Attié-Bitach T, Wurst W, Katsanis N, Ueffing M, Lickert H. (2010). "Pitchfork regulates primary cilia disassembly and left-right asymmetry.", Dev Cell. 2010 Jul 20;19(1):66-77.

Hauck SM, Dietter J, Kramer RL, Hofmaier F, Zipplies JK, Amann B, Feuchtinger A, Deeg CA, Ueffing M. (2010). "Deciphering membrane-associated molecular processes in target tissue of autoimmune uveitis by label-free quantitative mass spectrometry.", Mol Cell Proteomics. 9:2292-305

Hauck SM, Gloeckner CJ, Harley ME, Schoeffmann S, Boldt K, Ekstrom PA, Ueffing M. "Identification of paracrine neuroprotective candidate proteins by a functional assay-driven proteomics approach.", Mol Cell Proteomics. 2008 Jul;7(7):1349-61.

Deeg CA, Raith AJ, Amann B, Crabb JW, Thurau SR, Hauck SM, Ueffing M, Wildner G, Stangassinger M. "CRALBP is a highly prevalent autoantigen for human autoimmune uveitis.", Clin Dev Immunol. 2007;2007:39245.

Paquet-Durand F, Silva J, Talukdar T, Johnson LE, Azadi S, van Veen T, Ueffing M, Hauck SM, Ekström PA. "Excessive activation of poly(ADP-ribose)polymerase contributes to inherited photoreceptor degeneration in the retinal degeneration 1 mouse.", J Neurosci. 2007 Sep 19;27(38):10311-9.

den Hollander AI, Koenekoop RK, Mohamed MD, Arts HH, Boldt K, Towns KV,Sedmak T, Beer M, Nagel-Wolfrum K, McKibbin M, Dharmaraj S, Lopez I, Ivings L,Williams GA, Springell K, Woods CG, Jafri H, Rashid Y, Strom TM, van der Zwaag B,Gosens I, Kersten FF, van Wijk E, Veltman JA, Zonneveld MN, van Beersum SE, Maumenee IH, Wolfrum U, Cheetham ME, Ueffing M, Cremers FP, Inglehearn CF, Roepman R. (2007). "Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis.", Nat Genet. Jul;39:889-95.