Project abstract

Cataract is a major cause of blindness worldwide, either as a result of age-related degenerative modifications, or genetic mutations, causing abnormal aggregation of eye lens crystallins. While age-related cataracts occur only in adults, inherited congenital cataracts manifest in early childhood. Currently the only effective treatment that can be applied for cataract is surgery, without any possibility of prevention. A complete elucidation of the molecular mechanism of crystallin aggregation is essential for understanding cataract formation.

The proposed research aim to investigate the molecular aggregation pathway of the Pro23Thr mutation in human gamma D-crystallin (hγD-P23T), as a representative variant causing congenital cataract. We plan to get new insights into the interaction mechanism inside the eye lens causing hγD-P23T aggregation, and its escape from chaperone surveillance. In addition, potential inhibitors interfering with the phase-separation mechanism, will be tested against hγD-P23T aggregation.

This work will involve methods that allow structural, and interactions details inside eye lens, primarily NMR spectroscopy, ITC, in silico inhibitors screening, aggregation supperssion bioassay in vitro, and molecular docking. Combining this integrated structural biology approach to study cataract, is a promising perspective for the anti-cataract drug development.