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

正常的血细胞产生发生在骨髓中，并在衰老过程中恶化，并因血癌的发展而受损。在这个项目中，我们将研究正常的血细胞生产是如何调节的，特别是调节基因如何形成相互关联的网络，使单个干细胞可以产生多种不同类型的血细胞。我们将利用这一知识来研究克隆性造血(CH-a白血病前期综合征)和骨髓纤维化(MF-一种导致骨髓衰竭的高增殖性疾病)中血细胞的产生是如何受到干扰的。为此，我们将设计和开发新的遗传小鼠模型，准确复制导致人类CH和MF的遗传事件。由于CH和MF在老年人中发生的频率更高，我们将使用这些模型来确定在衰老过程中发生的生理变化，这些变化有助于扰乱造血干细胞内的正常调控网络，并导致疾病的发展。识别出的分子或细胞类型随后将被适当的药物(将在必要时开发)作为靶点，以证明它们具有对抗疾病发展的能力。通过这种方式，我们希望为这些血液疾病开发新的治疗策略。

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.