Targeted protein degradation in human disease models
Supervisor: Dr Andrew Wood
Genome editing has transformed our ability to make human disease models. However, genetic manipulation occurs at the DNA level, whereas proteins mediate most biological functions. This limits the ability to understand disease mechanisms, identify therapeutic targets and model therapeutic interventions.
This project will focus on degron-tagging, a technique which harnesses the latest advances in the engineering of genomes, proteins and small molecules to enable direct and chemically inducible degradation of target proteins via the ubiquitin-proteasome system. Degron tagging is already widely used in cell culture, and we have been among the first in the world to adapt this technique for use in mammalian tissues. This project will take advantage of new transgenic tools generated in our laboratory to develop better methods for degrading human disease proteins in tissues and organoids, and better preclinical models for protein degrader drugs.
Macdonald L, Taylor G, Brisbane J, Christodoulou E, Scott L, Von Kriegsheim A, Rossant J, Gu B, Wood AJ Rapid and specific degradation of endogenous proteins in mouse models using auxin-inducible degrons. Elife. 2022 Jun 23;11:e77987. doi: 10.7554/eLife.77987.