Development of new CRISPR/Cas9-based tools to study drug interactions and endocytic pathogens
My lab has developed a series of new functional genomics tools, and applied them to study (1) drug interactions and (2) various pathways of cellular uptake by endocytic pathogens.
For example, we have used genome-wide shRNA and CRISPR/Cas9 screens to identify novel drug targets, with highly complementary results using the two technologies. We have extended this work to create a platform for high-throughput pairwise expression of sgRNAs directed against known drug targets, and used it to identify rare synthetic lethal gene combinations. The corresponding drugs exhibit expected synergy, and show promise in a leukemia model. More generally, this platform can be used to create CRISPR-based systematic genetic interaction maps for any process of interest. In order to more precisely study how drugs interact with their targets, we have also developed a strategy to use dCas9 to redirect the somatic hypermutation machinery used in antibody affinity maturation; this can be used to evolve new protein variants with altered activities and drug binding properties.
Most recently, we have used these tools to systematically identify factors required for endocytosis and phagocytosis of diverse pathogens. The goal is to both understand endocytic trafficking and to identify new drug targets for intervention.