Interrogating the b-catenin interactome for novel modulators of Wnt signaling.

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Adult stem cells maintain and regenerate tissue systems throughout the life of an organism. Haematopoietic stem cells (HSC) generate and replenish the blood system in the bone marrow and have great potential to be exploited therapeutically for transplantation purposes. Specifically, factors that promote the ex vivo expansion, maintenance and storage of HSCs are highly desirable in the treatment of multiple bone marrow diseases including leukaemia, anaemia, myeloproliferative disorders, myelodysplastic syndrome, autoimmune conditions, HIV infection and sickle cell disease. Canonical Wnt/Beta-catenin signalling is an evolutionary conserved signal transduction cascade implicated in both normal development and disease. In particular, adult stem cells utilise this pathway to drive self-renewal and/or proliferation decisions. Wnt signalling is known to drive the self-renewal and proliferation of HSCs, however the molecular mechanisms driving these processes are not well understood. The central mediator of the pathway, Beta-catenin, first stabilises in the cytoplasm before translocation into the nucleus where is serves as a transcriptional co-activator of Wnt target genes. Beta-catenin's stability, localisation and activity is governed heavily through protein-protein interactions and recent studies have demonstrated that Beta-catenin's interactome (and indeed overall Wnt-responsive proteome) varies considerably between cell types. The aim of this project is to characterise the Beta-catenin interaction network in blood cells for the purposes of identifying novel regulators of Wnt signalling that drive self-renewal/proliferation fate in HSC. The student will use a combination of computational and wet lab techniques to both identify and validate tissue-specific interaction partners (see Training and Methods below). The broader fundamental impact of this project will be in understanding how the core biochemical mechanisms of Wnt signalling are modulated through tissue or context specific interactions allowing Wnt signalling to function in diverse cells/tissues. This project may also lead to industrial collaboration for the development of novel agents for targeting Wnt signalling and associated proteins of interest.