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

点击翻译按钮获取中文摘要

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.