The scientist: Dr. Francisco Olmo will exploit high-throughput genetic technologies to identify genes involved in resistance to anti-T.cruzi lead compounds belonging to the GSK Chagas Box recently published. Francisco is a Postdoctoral Researcher at LSHTM, working under the supervision of Prof. John Kelly. He is a biochemist/molecular biologist by training with first-hand experience in kinetoplastid biology. Francisco has carried out placements in several international labs.
The sponsor: London School of Hygiene and Tropical Medicine (Department of Pathogen Molecular Biology)
Foundation funding: The Foundation is providing £176,250 in support, including co-funding from the European Union through its FP7 COFUND programme.
GSK’s contribution: GSK will provide its experience in lead discovery and compound profiling stemming from phenotypic hits, as recently published (Scientific Reports 5:8771, March 2015. DOI: 10.1038/srep08771). This experience will be leveraged in terms of examining phenotypically transformed parasite clones selected by the scientist for resistance to compounds in the Chagas-Box at GSK lab. Extensive screening by High Content Imaging Assays will be carried out against intra and extracellular forms.
Project Description: The aim of the project will be to add value to the lead optimization process by identifying the intra-parasite targets of compounds showing most therapeutic promise, deciphering their mechanisms of action, and assessing the potential for resistance.
Identification of genes involved in resistance to novel compounds from the HTS formerly prosecuted at GSK will be approached through complementary high-throughput genetic methodologies, such as RITseq in T. brucei, CRISPR/cas9 in T. cruzi and construction of a T. cruzi cosmid over-expression library. The set of genetic constructs will be screened against GSK Chagas Box in order to assess the modes of action and/or resistance mechanisms of lead compounds in T. cruzi. Furthermore, in vivo screening can be undertaken to assess physiological relevance