Unfolded Protein Response as a Therapeutic Target for ADRP Animal Models This project 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. Retinitis pigmentosa (RP) is the most common inherited form of blindness, affecting about 1 in every 4000 people in all ethnic groups worldwide. RP can be transmitted either as an autosomal dominant (ADRP), autosomal recessive (ARRP), or X-linked trait. More than 100 mutations in rhodopsin account for approximately 30% of ADRP cases with varying severity of visual impairment. Misfolded opsin 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. Although supplementation with vitamin A may be beneficial in some cases, currently, there is no effective pharmacological therapy for ADRP. Therefore, the major objective of this proposal 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, unlimited by different localizations of rhodopsin mutations (P23H and T17M). In two mouse models of ADRP, we plan to reprogram the ER stress signaling by viral delivery of the molecular chaperone GRP78/BiP and delivery of small interfering siRNAs targeting caspase-7, caspase-12 and pro-apoptotic CHOP/GADD153 mRNAs to diminish the level of apoptosis in ADRP photoreceptors. For each ADRP model, we plan to: (1) modulate the UPR in favor of activation of pro-survival pathway by over- expression of BiP protein;(2) suppress apoptosis by diminishing levels of activated caspase-7 and caspase-12 and (3) inhibit the CHOP-associated apoptosis by targeting CHOP mRNA. We will monitor survival of photoreceptors using electroretinography and morphometry and will measure the activation of the ER stress and apoptosis using specific antibodies and RT-PCR. We will also measure improvement in vision using Optometry, a technique that can evaluate both acuity and contrast sensitivity in mice. We anticipate that the success of this approach will also require the appropriate combination of AAV serotype, vector dosage, photoreceptor specific promoter and optimized expression for the chaperone BiP. While AAV mediated gene transfer is being developed for treatment of RP, the suppression of ER stress and of apoptosis using chaperones is novel. This approach may overcome the genetic diversity of this disease and reveal the pathways of cell death that lead from mutation to retinal degeneration.

Public Health Relevance

Our goal is to design gene therapy for blinding disorder known as Autosomal Dominant Retinitis Pigmentosa (ADRP). We plan to study cellular mechanisms involved in photoreceptor death and develop a gene therapy based on the blockage of apoptosis in ADRP photoreceptors. Using a harmless virus, we plan to deliver molecular chaperon BiP and small RNA molecules to improve function and structure of photoreceptors and also intend to study the mechanism by which these therapeutic molecules provide therapy.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Biology and Diseases of the Posterior Eye (BDPE)
Program Officer
Shen, Grace L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Alabama Birmingham
Schools of Optometry/Opht Tech
United States
Zip Code
Sizova, Olga S; Shinde, Vishal M; Lenox, Austin R et al. (2014) Modulation of cellular signaling pathways in P23H rhodopsin photoreceptors. Cell Signal 26:665-72
Choudhury, Shreyasi; Nashine, Sonali; Bhootada, Yogesh et al. (2014) Modulation of the rate of retinal degeneration in T17M RHO mice by reprogramming the unfolded protein response. Adv Exp Med Biol 801:455-62
Wang, Xiaoqin; Wang, Guibo; Kunte, Mansi et al. (2013) Modulation of angiogenesis by genetic manipulation of ATF4 in a mouse modulation of angiogenesis by genetic manipulation. Invest Ophthalmol Vis Sci 54:5995-6002
Nashine, Sonali; Bhootada, Yogesh; Lewin, Alfred S et al. (2013) Ablation of C/EBP homologous protein does not protect T17M RHO mice from retinal degeneration. PLoS One 8:e63205
Gorbatyuk, Marina; Gorbatyuk, Oleg (2013) Review: retinal degeneration: focus on the unfolded protein response. Mol Vis 19:1985-98
Gorbatyuk, Marina S; Gorbatyuk, Oleg S (2013) The Molecular Chaperone GRP78/BiP as a Therapeutic Target for Neurodegenerative Disorders: A Mini Review. J Genet Syndr Gene Ther 4:
Choudhury, S; Bhootada, Y; Gorbatyuk, O et al. (2013) Caspase-7 ablation modulates UPR, reprograms TRAF2-JNK apoptosis and protects T17M rhodopsin mice from severe retinal degeneration. Cell Death Dis 4:e528
Gorbatyuk, Marina S; Gorbatyuk, Oleg S; LaVail, Matthew M et al. (2012) Functional rescue of P23H rhodopsin photoreceptors by gene delivery. Adv Exp Med Biol 723:191-7
Mao, Haoyu; Gorbatyuk, Marina S; Rossmiller, Brian et al. (2012) Long-term rescue of retinal structure and function by rhodopsin RNA replacement with a single adeno-associated viral vector in P23H RHO transgenic mice. Hum Gene Ther 23:356-66
Gorbatyuk, Marina S; Shabashvili, Arseniy; Chen, Weijun et al. (2012) Glucose regulated protein 78 diminishes ?-synuclein neurotoxicity in a rat model of Parkinson disease. Mol Ther 20:1327-37

Showing the most recent 10 out of 13 publications