Discovering novel modulators of Wnt signalling and their impact on the haematopoietic system

Haematopoietic stem cells (HSC) generate and replenish the blood system in the bone marrow and have great potential to be exploited therapeutically. 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 anaemia, myeloproliferative disorders, myelodysplastic syndrome, cancer, autoimmune conditions, HIV infection and sickle cell disease. 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, proliferation or differentiation decisions. Wnt signalling is known to drive the ex vivo self-renewal and proliferation of HSCs, however compounds and reagents for manipulating this process in the clinic are limited. Recently, the Morgan group (Sussex), and Baud/Ewing groups (Southampton) have undertaken cutting-edge "proximity labelling" mass spectrometric analysis to discover novel regulators of Wnt signalling in multiple tissues (including haematopoietic) and unveiled a plethora of novel candidate molecules that may regulate the pathway. The aim of this project is to understand how these molecules impact Wnt signalling pathway, and design new pharmacological strategies for HSC expansion. This will be broken down into 3 critical objectives;
1. Validating the impact of putative Wnt-modulating molecules on Wnt signalling output in haematopoietic cells.
2. Assessing the efficacy of novel compound design/repurposing on Wnt signalling level in blood cells.
3. Characterising the impact of novel compounds on the ex vivo expansion and maintenance of human cord blood derived HSCs.
PhD candidates will adopt a combination of cellular (primary tissue culture, lentiviral transduction, flow cytometry) molecular (Western blotting, PCR, qRT-PCR) and chemical (biophysical binding assays, computational structural studies) techniques to interrogate the main objectives of this study.