Functional analysis of the Notch signalling pathway in the differentiation and maintenance of pituitary progenitor cells

许多对正常身体功能至关重要的过程，如生长、应对压力的能力、性器官发育、新陈代谢和产奶，都由脑下垂体控制。这个器官位于大脑的底部，通过释放六种不同的激素来调节这些身体功能。脑垂体腺的形成发生在胎儿的发育过程中。这个过程需要一组特定的基因来塑造脑下垂体，并允许荷尔蒙分泌细胞的出现。这些脑下垂体形成基因的变化导致新生儿脑下垂体发育不良。在严重的情况下，如果脑下垂体未能完全形成(全垂体功能减退症)，这些婴儿病情严重，在某些情况下无法存活。我们正在研究属于Notch信号通路的基因。在大脑、皮肤、骨骼和许多其他组织的发育过程中，这些基因是细胞分化的重要调节因素。然而，Notch信号基因在脑下垂体发育中的作用尚不清楚。我们首次证明了这些基因在脑下垂体发育过程中是活跃的。为了测试这些基因在脑下垂体中的功能，我们将产生缺乏或不适当激活这些基因的小鼠模型。我们的结果将为深入了解Notch信号基因在小鼠和人类脑下垂体发育中的作用提供依据。在这个项目中，我们还希望鉴定出脑下垂体中能够产生多种激素分泌细胞类型的细胞。这些干细胞具有重要的临床意义，因为它们为开发治疗人类垂体疾病的新疗法提供了一条途径，该疗法基于用功能干细胞来源的组织替代有缺陷的垂体组织。

Many of the processes that are essential for normal bodily function such as growth, the ability to cope with stress, sexual organ development, metabolism and milk production, are controlled by the pituitary gland. This organ is located at the base of the brain and regulates these bodily functions through the release of six different hormones. Formation of the pituitary gland occurs during development of the foetus. This process requires a specific set of genes that shape the pituitary and allow the hormone secreting cells to arise. Changes in these pituitary formation genes results in underdevelopment of the pituitary in newborn babies. In severe cases, where the pituitary has failed to form completely (panhypopituitarism), these babies are extremely ill and in some instances do not survive. We are studying the genes that belong to the Notch signalling pathway. These genes are important regulators of cell differentiation during the development of the brain, skin, bone and many other tissues. However, the role of the Notch signalling genes in pituitary development is not known. We have shown for the first time that these genes are active during pituitary development. To test the function of these genes in the pituitary, we will generate mouse models that either lack or inappropriately activate these genes. Our results will provide insight into the role of Notch Signalling genes in pituitary development in mice and humans. In this project, we also hope to identify cells in the pituitary that are able to give rise to multiple hormone secreting cell types. These stem cells are of significant clinical importance as they provide an avenue for the development of novel therapies for pituitary disorders in humans, based on the replacement of defective pituitary tissue with functional stem cell derived tissue.