Audrey M. Bernstein, PhD
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 World Health Organization estimates that 23 million people suffer from unilateral vision loss due to corneal disease. Causes of blindness from corneal disease include infection, inflammation, ulcers, and trauma. The cornea refracts light as it enters the eye so that a properly focused image reaches the retina. 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. RNA sequencing of myofibroblasts revealed significant changes in the expression of genes coding for 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 self-delivery siRNAs to promote regenerative healing and prevent scarring in vivo.
Autophagic Dysfunction in Exfoliation Glaucoma
Our work on Exfoliation glaucoma (XFG) also has broad consequences for the prevention of blindness. 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 exfoliation glaucoma patients. Our studies are the first to identify an age-related cellular defect in the autophagy system in patient-derived XFG cells. This project will interrogate the basic mechanisms leading to protein aggregate formation and expulsion from cells, and test novel therapies on patient-derived cells to reverse XFG pathology.