Kalzium-Dynamik in degenerierenden Photorezeptoren

• Antragsteller: Professor Dr. Thomas Euler; Professor Dr. Francois Paquet-Durand
• Fachliche Zuordnung: Molekulare Biologie und Physiologie von Nerven- und Gliazellen ; Augenheilkunde
• Förderung: Förderung von 2014 bis 2019
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 266705556

• Erstellungsjahr: 2019

Zusammenfassung der Projektergebnisse

Hereditary retinal degenerations (RD) constitute one of the leading causes of blindness in the developed world. These are at present untreatable and the underlying neurodegenerative mechanisms are unknown even though the genetic causes are often established. Elevated levels of cyclic guanosine monophosphate (cGMP) are responsible for photoreceptor cell death in different animal models for human RD, moreover, in photoreceptors, cGMP-signalling is intricately linked to Ca2+ signalling via the activity of cGMP-gated Ca2+ CNG channels. The project investigated Ca2+-signalling and its dynamics in photoreceptor degeneration using in vivo, ex vivo, and in vitro techniques and comparing different mouse models for both primary rod and cone photoreceptor degeneration. The data generated has improved our understanding of the importance of Ca2+ for photoreceptor cell death, notably by producing estimates of Ca2+ levels in dying photoreceptors, showing higher Ca2+ fluctuations in mutant photoreceptors, implicating calpain-2 in the degenerative process, and establishing a likely sequence of degenerative events triggered by high Ca2+. Another important outcome of the project was to establish that primary rod or cone photoreceptor degeneration was likely caused by Ca2+-calpain-dependent, non-apoptotic cell death mechanisms, while the secondary loss of cones appeared to follow a classical apoptotic process. In addition, the data and ideas generated during the project have led to several follow-up projects and grant applications. Particularly, there are two DFG funded projects that continue aspects of this project: The first is investigating CNG channel targeting approaches as a means to lower intracellular Ca2+ levels and protect photoreceptors. The second is developing liposomal nanocapsules to deliver therapeutic compounds (e.g. CNG channel inhibitors, anti-sense oligonucleotides) to the photoreceptors of the retina in vivo. A European Union funded innovative training network (ITN) additionally aims to develop new biomarker approaches, approaches which in part are based on alterations of photoreceptor Ca2+-signalling (H2020-MSCA-ITN-765441; www.transmed.eu).

Projektbezogene Publikationen (Auswahl)

• Calcium dynamics change in degenerating cone photoreceptors. Hum Mol Genet. 25(17):3729-3740. 2016
  Kulkarni M, Trifunović D, Schubert T, Euler T, Paquet-Durand F
  
• Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration. Sci Rep. 6:39537, 2016
  Sahaboglu A, Barth M, Secer E, Amo EM, Urtti A, Arsenijevic Y, Zrenner E, Paquet-Durand F
  
• Temporal progression of PARP activity in the Prph2 mutant rd2 mouse: Neuroprotective effects of the PARP inhibitor PJ34. PLoS One. 12(7):e0181374, 2017
  Sahaboglu A, Sharif A, Feng L, Secer E, Zrenner E, Paquet-Durand F
  
• Combination of cGMP analogue and drug delivery system provides functional protection in hereditary retinal degeneration. PNAS USA. 115(13):E2997-E3006, 2018
  Vighi E, Trifunović D, Veiga-Crespo P, Rentsch A, Hoffmann D, Sahaboglu A, Strasser T, Kulkarni M, Bertolotti E, van den Heuvel A, Peters T, Reijerkerk A, Euler T, Ueffing M, Schwede F, Genieser HG, Gaillard P, Marigo V, Ekström P, Paquet-Durand F
  
• A retinal model of cerebral malaria. Sci Rep. 9(1):3470, 2019
  Paquet-Durand F, Beck SC, Das S, Huber G, Le Chang, Schubert T, Tanimoto N, Garcia-Garrido M, Mühlfriedel R, Bolz S, Hoffmann W, Schraermeyer U, Mordmüller B, Seeliger MW
  
• Cellular mechanisms of hereditary photoreceptor degeneration - Focus on cGMP. Prog Retin Eye Res. 100772
  Power MJ, Das S, Schütze K, Marigo V, Ekström P, Paquet-Durand F
  
• Entwicklung von cGMP Analoga zur pharmakologischen Behandlung von neurodegenerativen Netzhauterkrankungen. Klin Monbl Augenheilkd. 236(3):253-260, 2019
  Fischer DM, Paquet-Durand F
  
• Systematic spatio-temporal mapping reveals divergent cell death pathways in three mouse models of hereditary retinal degeneration
  Power MJ, Rogerson LE, Schubert T, Berens P, Euler T, Paquet-Durand P
  
• The cGMP Pathway and Inherited Photoreceptor Degeneration: Targets, Compounds, and Biomarkers. Genes (Basel). 10(6): 453. 2019
  Tolone A, Belhadj S, Rentsch A, Schwede F, Paquet-Durand F