All ETDs from UAB

Advisory Committee Chair

Marina Gorbatyuk

Advisory Committee Members

Alecia Gross

Shu-Zhen Wang

Steven Pittler

Zsuzsanna Bebok

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) School of Optometry

Abstract

Retinitis pigmentosa (RP) is a group of retinal degenerative diseases characterized by the loss of rod photoreceptor cells that can be followed by cone degeneration eventually culminating in total photoreceptor cell loss. This disease affects approximately 1.5 million people worldwide and can be transmitted in an autosomal dominant (ADRP) manner accounting for nearly 30% of all RP cases. Dominant rhodopsin mutations have been divided into class I and class II based on the folding of rhodopsin protein, thermal stability, and chromophore regeneration. A threonine-17-methionine (T17M) mutation in rhodopsin is a class II mutation, characterized by a thermal instability/folding defect and minimal regeneration with the chromophore. Misfolded opsin interferes with the trafficking of wild-type rhodopsin, causing accumulation in the endoplasmic reticulum (ER) and stimulation of a signal transduction cascade known as the Unfolded Protein Response (UPR). If not deactivated, this pathway triggers photoreceptor death, presumably through triggering apoptosis. T17M mutant rhodopsin mice have become a valuable animal model for the study of ADRP. In these mice we have demonstrated that PERK (RNA-activates protein kinase-like ER kinase) signaling, is upregulated leading to an increase in phosphorylated (p) translational eukaryotic initiation factor 2α (eIF2α), ATF4 (Activating transcription factor 4) and CHOP (C/EBP Homologous Protein) mRNA, starting at postnatal day (P) 18. Manipulating ATF4 and CHOP expression in a mouse model of retinal degeneration with UPR activation, we demonstrated for the first time that ATF4 overexpression accelerates retinal degeneration through CHOP and caspase induced cell death. In contrast, genetic ablation of one allele of ATF4 and CHOP altogether mitigates retinal degeneration and provides long term rescue. Several studies have suggested that Caspase-12 acts as an initiator caspase during ER stress-induced apoptosis, activating an effector caspase-3 or -7 which then cleaves key substrates required for normal cellular functions, thus leading to apoptosis. Here, we validated caspase-12 as a therapeutic target, ablation of which significantly protects T17M photoreceptors from progressing degeneration. Although the inhibition of apoptotic activity alone was not sufficient to rescue T17M photoreceptors, in combination with other non-apoptotic targets, caspase-12 could be used to treat inherited retinopathy.

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Optometry Commons

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