Control of pituitary stem cell activity in human and mouse through modulation of YAP/TAZ signalling

脑下垂体是位于大脑下方的一个器官，控制着人类和动物的重要功能，如生长、新陈代谢、我们对压力的反应以及青春期和繁殖。它是通过产生一种叫做垂体激素的因子来实现的，这种因子被释放到血液中并分布到全身。荷尔蒙水平的不平衡会导致严重的健康问题，影响垂体调节的功能。垂体疾病可导致正常生产和分泌中断，其中一种情况称为垂体功能减退症，即器官功能衰竭，激素分泌过少，或垂体肿瘤，可能产生过多的激素，但也会挤压周围健康的垂体，导致垂体功能减退，损害大脑并影响视力。此外，随着年龄的增长，激素水平会下降，导致身体功能的正常衰退，这是衰老的特征。由于维持稳定的激素水平是很重要的，垂体在一生中包含并补充负责产生激素的专门细胞。这些产生激素的细胞来源于表达SOX2因子的干细胞。我们和其他人的研究表明，这些SOX2干细胞的功能随着小鼠年龄的增长而下降，这可能导致垂体功能的丧失。此外，研究表明SOX2干细胞功能异常可导致垂体肿瘤。我们研究的主要目标是研究控制SOX2干细胞功能的机制，并最终发现在垂体疾病中激活或抑制SOX2功能的新方法。我们在小鼠身上的研究已经为理解SOX2干细胞做出了重大贡献，并发现了其他可以激活这些干细胞并刺激它们分裂的因素，这些因素要么产生新的激素分泌细胞，要么通过不受控制的分裂导致垂体肿瘤。在本提案中，我将结合各种最先进的技术来解剖小鼠中这两种相反功能的机制，此外，我将研究这些机制是否在人类垂体中保守。如果我们想开发和应用再生医学方法治疗垂体功能减退症或衰老患者，并抑制垂体肿瘤中的这种激活，后者是必要的一步。

The pituitary gland is an organ situated beneath the brain that controls important functions in humans and animals such a growth, metabolism, our response to stress as well as puberty and reproduction. It does so by producing factors that are called pituitary hormones, which are released into the blood and distributed throughout the body. An imbalance in hormone levels can result in serious health problems affecting the functions regulated by the pituitary. Disruption of the normal production and secretion can develop as a result of pituitary diseases, among which a condition called hypopituitarism where the organ fails and too little hormone is secreted, or pituitary tumours which may produce excess hormones but also crush surrounding healthy pituitary resulting in hypopituitarism as well as damaging the brain and affecting vision. In addition, the levels of hormones decline as we get older, contributing to the normal deterioration of bodily functions that characterise ageing. Since it is important to maintain steady hormone levels, the pituitary contains and replenishes specialised cells throughout life that are responsible for producing hormones. These hormone-producing cells are derived from stem cells that express a factor called SOX2. Our research and that from others has shown that the function of these SOX2 stem cells declines with age in mice, which may contribute to the loss of pituitary function. Additionally, it has shown that abnormal function of SOX2 stem cells can result in tumours of the pituitary. The main goal of our research is to study the mechanisms that control SOX2 stem cell function and to ultimately discover new ways to activate or inhibit SOX2 function in pituitary diseases as needed. Our research in mouse has already significantly contributed in understanding SOX2 stem cells and identified other factors that can activate these stem cells and stimulate them to divide, either to produce new hormone-secreting cells or to cause pituitary tumours by dividing uncontrollably. In this proposal, I will combine diverse state-of-the-art techniques to dissect the mechanisms underlying these two opposite functions in mouse and in addition, I will investigate whether such mechanisms are conserved in the human pituitary. The latter is a necessary step if we want to develop and apply regenerative medicine approaches to patients with hypopituitarism or during ageing, and to inhibit such activation in pituitary tumours.