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

该项目将研究改变Kit配体/SCF，血小板生成和TGF β信号传导以及炎性细胞因子对造血干细胞（HSC）的维持和分化的影响，以开发HSC隔室在整个衰老过程中所经历的变化的计算模型。该模型将利用物理科学和数学生物学的技术来描述HSC的内在变化（改变谱系偏倚，减少每次不对称分裂的细胞输出）如何与细胞生长抑制和炎症细胞因子产生的微环境和系统变化相互作用，以控制HSC池大小和血细胞产生。该模型将根据年轻和老年造血和基质细胞的单细胞数据的计算分析进行改进，以模拟老化过程中改变的配体受体偶联。使用相关通路（例如IL-6和TGF β信号传导）抑制剂的扰动分析将用于进一步验证模型。

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.