Defining the Haematopoietic System through Integrated Multi-Scale Analysis (360G-Wellcome-206328_Z_17_Z)

Biological processes operate at vastly different scales ranging from molecules to entire organs. However, relating molecular insights to whole tissue function remains difficult since biomedical research commonly focusses on just a single scale. The Göttgens group has taken advantage of new single cell profiling technologies to generate a comprehensive landscape of the transcriptional states that a blood stem cell may traverse through when it differentiates into the various blood lineages. Here it is proposed to use this single cell transcriptional landscape to connect different scales ranging from molecular to cellular to whole tissue function, and thus advance our understanding of cell fate decision making in blood stem and progenitor cells. Complementary experimental and computational approaches will address how molecular regulatory networks control cellular identity, and how tissue-scale computer models of the blood system can be grounded in comprehensive molecular information. The proposed experiments are designed to provide new leads for subsequent studies, including potential new therapeutic targets from analysis of pre-leukaemic models. Moreover, empowering single cell transcriptional landscapes to link "molecular" observations with the function of the entire haematopoietic system will generate a framework that is broadly applicable to advance our understanding of all normal and pathological organ systems.