Computational modelling of hematopoietic stem cell maintenance during physiological ageing inflammatory stress

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This project will examine the effects of altering Kit ligand/SCF, thrombopoietic and TGFbeta signalling, as well as inflammatory cytokines, on the maintenance and differentiation of hematopoietic stem cells (HSCs), in order to develop a computational model of the changes undergone by the HSC compartment throughout aging. The model will draw on techniques from the physical sciences and mathematical biology to depict how intrinsic changes to HSCs (altered lineage bias, diminished cellular output per asymmetric division) interact with microenvironmental and systemic changes to cytostatic and inflammatory cytokine production to control HSC pool size and blood cell production. The model will be refined based on computational analysis of single cell data from young and aged hematopoietic and stromal cells, in order to model altered ligand receptor couplings during ageing. Perturbation analysis using inhibitors of relevant pathways (e.g. IL-6 and TGFbeta signaling) will be used to further validate the model.