title: Modulation of the rate of retinal degeneration in T17M RHO mice by reprogramming the unfolded protein response.
abstract: The goal of this study is to validate whether reprogramming of the UPR via modulation of pro-apoptotic caspase-7 and CHOP proteins could be an effective approach to slow down the rate of retinal degeneration in ADRP mice. In order to pursue our goal we created the T17M RHO CASP7 and T17M RHO CHOP mice to study the impact of the CASP7 or CHOP ablations in T17M RHO retina by ERG, SD-OCT, histology and western blot analysis. The scotopic ERG demonstrated that the ablation of the CASP7 in T17M RHO retina leads to significant preservation of the function of photoreceptors compared to control. Surprisingly, the ablation of pro-apoptotic CHOP protein in T17M RHO mice led to a more severe form of retinal degeneration. Results of the SD-OCT and histology were in agreement with the ERG data. The further analysis demonstrated that the preservation of the structure and function or the acceleration of the onset of the T17M RHO photoreceptor degeneration occurred via reprogramming of the UPR. In addition, the CASP7 ablation leads to the inhibition of cJUN mediated apoptosis, while the ablation of CHOP induces an increase in the HDAC. Thus, manipulation with the UPR requires careful examination in order to achieve a therapeutic effect.
authors.affiliation: Department of Cell Biology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, USA, shreyasi.choudhury@live.unthsc.edu.
authors.forename: Shreyasi
authors.initials: S
authors.lastname: Choudhury
authors.forename: Sonali
authors.initials: S
authors.lastname: Nashine
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Bhootada
authors.forename: Mansi Motiwale
authors.initials: MM
authors.lastname: Kunte
authors.forename: Oleg
authors.initials: O
authors.lastname: Gorbatyuk
authors.forename: Alfred S
authors.initials: AS
authors.lastname: Lewin
authors.forename: Marina
authors.initials: M
authors.lastname: Gorbatyuk
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053179:Caspase 7 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004596:Electroretinography; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012243:Rhodopsin / Q000235:genetics* / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics*
chemical_list: C497250:Ddit3 protein, mouse; D051742:Transcription Factor CHOP; D012243:Rhodopsin; C505524:Casp7 protein, mouse; D053179:Caspase 7