Center for Biohealth, UNTHSC
Faculty and Staff
Marina Gorbatyuk, PhD
Assistant Professor, Department of Cell Biology and Anatomy, NTERI
Mansi Kunte, PhD
Postdoctoral Research Associate
About Our Lab
Our laboratory is focused on 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 rhodopsin that interferes with the trafficking of wild-type rhodopsin, accumulates in the endoplasmic reticulum (ER) and stimulates 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 lab 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 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 and rat models of ADRP. We also use a viral AAV-mediated delivery of therapeutic genes to transgenic mice and rats.
At this time, we are pursuing three major experimental directions.
Project 1: Identification of the role of molecular chaperone BiP in functional preservation of ADRP retina. We are specifically interested in therapeutic targeting of the upstream UPR marker (BiP/GRP78). 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 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) branch of the UPR in the same mouse model gives us opportunity to validate the UPR as a possible target for ADRP gene therapy.
Project 2. Identification of the impact of caspase-7 and caspase-12 in retinal degeneration of ADRP animal models. We are interested in therapeutic targeting of the downstream UPR markers (caspase-12, caspase-3/7). We have already found that caspase-7 is elevated in P23H RHO photoreceptors and binding of BiP protein to caspase-12 leads to functional preservation of P23H RHO photoreceptors. Therefore, now we want to define the contribution of these caspases in ADRP progression in mouse and rat retinas deficient in caspase-7 and caspase-12.
Project 3. Determination of the impact of pro-apoptotic CHOP protein in the deterioration of ADRP retina. We have found that modulation of the UPR leading to reduction of CHOP protein could be beneficial for ADRP retinas. Now we would like to explore the importance of CHOP protein in retinal degeneration to validate pro-apoptotic CHOP protein as a target for ADRP gene therapy.