Date of Award

8-1-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

Iok-Hou Pang

Second Advisor

Abbot F. Clark

Third Advisor

Robert J. Wordinger

Abstract

CCAAT/ enhancer binding protein (C/EBP) homologous protein (CHOP) is a pro-apoptotic, transcription factor, and an endoplasmic reticulum (ER) stress-induced marker of the unfolded protein response. The purpose of our study was to delineate the role of CHOP in photoreceptor and RGC death. We used CHOP knockout (Chop-/-) and C57BL/6J (WT) mice and the following two mouse models of retinal degeneration: the T17M RHO model and the retinal I/R model. We found that CHOP deficiency led to a significant reduction in ERG a-wave amplitudes and the thickness of the outer nuclear layer at P30. Also, we observed significant downregulation of mouse Rho, T17M RHO, Crx, Nrl, sXBP1 and P300 whereas the expression of peIF2α and Hdac1 was significantly increased in the ADRP mouse retina. CHOP was found to be upregulated in the RGCs 3 d after I/R and deficiency of CHOP significantly increased RGC survival at 3 d, 7 d, 14 d, and 28 d after I/R. RGC function was also found to be improved at 3 d and 7 d after I/R. These results indicate that 1) CHOP plays a cytoprotective role in T17M ADRP photoreceptors and ablation of CHOP does not prevent loss of photoreceptors and 2) CHOP knockout partially protects against loss of RGC number and function after retinal I/R. In conclusion, CHOP contributes significantly to the survival and death pathways of photoreceptors and RGCs and modulation of the CHOP-mediated apoptotic pathway could help in the development of plausible treatment strategies for retinal degenerative diseases.

Comments

Nashine, Sonali R., Role of C/EBP Homologous Protein in Photoreceptor and Retinal Ganglion Cell Death. Doctor of Philosophy (Biomedical Sciences), Aug 2014. Available online August 2015.

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