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Gorbatyuk Laboratory at the VSRC
UAB | Volker Hall Bld. | Rm 443| 1670 University Ave., | Birmingham AL | 35233| Lab Phone: (205) 934 6764.
About the Lab
Lab Members 427 small Our lab is concentrated on the study of the mechanisms of retinal degeneration and the elucidation of the role of the Unfolded Protein Response (UPR) in autosomal dominant retinitis pigmentosa (ADRP) pathogenesis and development of the gene therapy based on modulation of the UPR signaling markers. In particular, we study misfolded rhodopsins that interfere with the trafficking of the wild-type rhodopsin, accumulate in the endoplasmic reticulum (ER) and stimulate a signal transduction cascade known as the Unfolded Protein Response (UPR). If unchecked, this pathway triggers photoreceptor death, presumably through apoptosis. Therefore, the main focus of our research is to determine whether the gene therapy based on the re-programming of the ER stress response caused by aberrant rhodopsin is a viable treatment and is unlimited by different localizations of rhodopsin mutations. 
In our current study we  use genetic, biochemical, cell biological, physiological and morphometric approaches to dissect mechanisms of retinal degeneration and target the ER stress signaling to restore the photoreceptor cell homeostasis and balance in mouse ADRP models. We are specifically interested in therapeutic targeting of upstream (BiP/GRP78) and downstream (CHOP and caspase-7 and -12) branches of the UPR. Our studies to date indicate that over-expression of BiP protein in ADRP rat’s photoreceptors restores visual function. We have demonstrated that BiP chaperone reprograms the UPR favoring the survival of photoreceptors, blocks apoptosis, and, ultimately, preserves vision. We also have shown that this therapeutic effect is due to reduction of pro-apoptotic CHOP protein and photoreceptor apoptosis. We have detected complexes between BiP, caspase-12, and the BH3-only protein BiK that may contribute to the antiapoptotic activity of BiP. Therefore, reprogramming the upstream (BiP protein) and downstream (CHOP and Caspase-12) branches of the UPR in the same mouse model gives me opportunity to validate the UPR as a possible target for ADRP gene therapy.