The role of protein aggregation in eye disease:

The central goal of our lab is to prevent blinding eye disease. Our research is focused on promoting regenerative healing in the eye after wounding and targeting the cellular dysfunction that leads to glaucoma. The involvement of aberrant protein aggregation and ubiquitin-mediated pathways in these ocular pathologies is the focus of our studies.

Regenerative Healing in the Eye:Corneal scarring is one of the leading causes of blindness worldwide. The normal cornea is transparent, making it an important model system in which to study fibrotic scarring. Corneal scarring results from the persistence of myofibroblasts, cells that excessively contract tissue and secrete disorganized extracellular matrix. Genetic screening of myofibroblasts revealed significant changes in the gene expression of ubiquitin pathway components including increased expression of a subset of deubiquitinating enzymes (DUBs). Our studies are investigating the impact of DUBs in regulating scarring in the eye and testing the efficacy of targeting DUBs with siRNAs to promote regenerative healing and prevent scarring in vivo.

Autophagic Dysfunction in Exfoliation Glaucoma (XFG): In XFG, the leading identifiable cause of glaucoma, the eye accumulates protein aggregates that block the exit of fluid from the eye. We have discovered that a significant lysosomal/autophagy defect defines primary cells isolated from the eyes of XFG patients. This work interrogates the basic mechanisms leading to protein aggregate formation and expulsion from cells, and tests novel therapies on patient-derived cells to reverse XFG pathology.

Gillespie, S.R. Tedesco, L.J., Wang, L. and Bernstein, A.M. (2017). The deubiquitylase USP10 regulates integrin beta1 and beta5 and fibrotic wound healing. Journal of Cell Science, Oct 15, 130(20) (PMID: 28851806).

Wang, L., Pedroja, B.S., Meyers, E.E , Garcia, A.L, Twining, S.S., Bernstein, A.M. (2012) Degradation of internalized alphavbeta5 integrin is controlled by uPAR bound uPA: Effect on beta1 integrin activity and alpha-SMA stress fiber assembly, PLoS ONE, 7(3):e33915. (PMID: 22470492).

Want, A., Gillespie, S.R., Wang, Z., Gordon, R., Iomini, C. Ritch, R., Wolosin J.M., and Bernstein, A.M. (2016). Autophagy and Mitochondrial Dysfunction in Tenon Fibroblasts from Exfoliation Glaucoma Patients, PLoS ONE 11(7): e0157404. (PMID:27391778).

Wolosin, J.M., Robert Ritch, and Bernstein, A.M. (2016) Is Autophagy Dysfunction a Key to Exfoliation Glaucoma?Journal of Glaucoma, Dec 13. (PMID: 27977481).