Pleasant news, Today I have been awarded a MRC Career Development Award to conduct an independent research project at the University of York.
Title:
Signalling and regulation of Autophagy-related pathways during cellular Differentiation of African trypanosomes.
Project summary:
Autophagy and lysosome exocytosis are essential pathways that share molecular machinery and regulate the dynamic composition of lysosomes, central organelles for the homeostasis, cell survival and cell differentiation. Therefore, studying the regulation of these pathways is of a major importance to understand the complex mechanisms leading to the dynamic turnover of molecules in lysosomes. This project aims to decipher the regulation of autophagy and lysosome exocytosis and potential interplay during the Trypanosoma brucei differentiation. To understand how trypanosomes maintain homeostasis and adapt to different hosts is of paramount importance for animal and human health. These organisms are likely to have evolved alternative approaches since, for example, autophagy initiation is independent from or the are lacking essential protein kinases classically found in model organisms.
By coupling a high-throughput live imaging system with a kinome-wide RNAi screen, we will identify all kinases implicated in the regulation of autophagy in T. brucei. We will then reveal the dynamic (phospho-)proteomes of autophagy and lysosome exocytosis using a proximity labelling system. Direct interactions of these components with the identified kinases and their interplays between both pathways will be investigated by CRISPr/Cas9 knock-outs, kinase assays and mass spectrometry. Thereafter, we will decipher their role during tissue invasion and the quorum-sensing dependent differentiation, in the mammal host, and differentiation in the insect-vector of T. brucei, using relevant in vitro and in vivo models.
By demonstrating how phosphorylation controls autophagy, exocytosis and differentiation, this project will provide a better understanding of how trypanosome parasites adapt to, and persist in the different hosts encountered during their complex lifecycles. Additionally, where core components are conserved, this project may prove informative for other eukaryotes and neurodegenerative diseases, for example.
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