Targeting autophagy for the treatment of osteoarthritis - Phase II: Drug screen
Ghada Alsaleh, University of Oxford
Active: 2021.01.01 - 2021.09.30
UK SPINE Scientific Liaison: Monica Spisar
Autophagy is the main cellular bulk degradation pathway. Biological aging and specific diseases such as osteoarthritis are characterized in part by loss of autophagic efficacy.
TFEB is a master regulator of autophagy and lysosomal biogenesis. The researchers have previously identified a novel signalling pathway for inducing autophagy via post-translational donation of spermidine’s aminobutyl moiety to a specific lysine on eIF5A, known to regulate TFEB. Spermidine, however, is not a good candidate for development as an FDA approved therapeutic as it is too pleiotropic, but the eIF5A/TFEB pathway discovered may contain key drug targets. This second phase of the overarching project aims to identify drugs that increase TFEB expression.
The flow cytometry read-out used in phase I (CRISPR-cas9 screen) will be used, followed by a high throughput screen using a structural diversity set small (25,000) compound library. Compounds that increase TFEB protein (synthesis or activity) with concurrent evidence of increased autophagy will be validated by high content imaging.