Hierarchical organization of haematopoietic stem- and progenitor cell populations during steady state and stress haematopoiesis

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Normal blood cell production occurs in the bone marrow and deteriorates during ageing and is impaired by blood cancer development. In this program we will study how normal blood cell production is regulated, and in particular how regulatory genes form interlinked networks that allow the many different blood cell cell types to be generated from a single stem cell. We will use this knowledge to investigate how blood cell production is perturbed in clonal hematopoiesis (CH – a preleukemic syndrome) and myelofibrosis (MF – a hyperproliferative disorder that leads to bone marrow failure). For this purpose, we will design and develop new genetic mouse models that accurately replicate the genetic events that cause CH and MF in humans. As both CH and MF occurs more frequently in the elderly, we will use these models to to identify the physiological changes that occur during ageing that contribute to perturbation of the normal regulatory networks within hematopoietic stem cells and lead to disease development. The identified molecules or cell types will then be targeted with appropriate drugs (which will be developed in necessary) for their ability to counteract disease development. In this manner we hope to develop new therapeutic strategies for these blood disorders.