Function and Regulation of the Pituitary Stem Cell Compartment in Mammals

脑下垂体是代谢、繁殖、生长和应激反应等生理过程的中枢调节器。垂体前叶负责六种激素的持续产生，当负责这些激素产生的特殊细胞群耗尽或受损时，激素水平就会不足，这种情况被称为垂体功能减退症。每4000人中就有1人患有此病，发病率和死亡率都很高。已知的例子是遗传性侏儒症，由于缺乏生长激素导致孩子无法茁壮成长或无法进入青春期，这是由于缺乏促性腺激素引起的。同样，脑下垂体细胞的过度增殖会导致肿瘤，进而损害健康的垂体组织，导致垂体功能低下，这也可能由手术和治疗期间的损伤引起。这些肿瘤大多数对幸存者的生活质量造成毁灭性影响，给家庭、护理人员和社会服务造成沉重负担。通常，这些患者在就业和成为积极的社区成员方面遇到困难。我的研究旨在更好地理解这些人类疾病是如何产生的基础生物学，最终目标是开发更安全、更好的治疗方法。脑下垂体含有干细胞，在一生中产生新的激素细胞。然而，这些细胞如何参与腺体的持续功能以及控制细胞规格的分子仍然未知。我的研究表明，WNT信号因子是协调正常发育的一组重要蛋白质，在垂体干细胞区室的调节中发挥作用。该提案旨在以脑垂体为模型，深入了解干细胞生物学。结合小鼠遗传学和该器官的实时成像，我们将揭示垂体干细胞的功能，以及WNT信号如何通过提供指导性线索参与调节细胞决策。由于WNT通路与干细胞参与许多人类肿瘤和癌症密切相关，我的研究将对阐明干细胞可能导致这些疾病的不同作用产生重要影响。这项工作将使科学界受益，因为它提供了干细胞生物学的进展，这反过来又可以导致更好的疾病管理和治疗毁灭性的人类疾病。

The pituitary gland is a central regulator of physiological processes such as metabolism, reproduction, growth and the stress response. The anterior pituitary is responsible for the continuous production of six hormones, and when the specialised cell populations responsible for their production are depleted or impaired, levels of hormone can become insufficient, a condition known as hypopituitarism. This condition affects up to 1 in 4000 individuals and is associated with considerable morbidity and mortality. Known examples are genetic dwarfism, due to lack of growth hormone leading to failure of the child to thrive or failure to enter puberty, which is caused by lack of gonadotrophins. Similarly an over-proliferation of cells in the pituitary gland leads to tumours, which in turn can damage healthy pituitary tissue resulting in hypopituitarism, something which can also develop from damage during surgery and treatment. Most of these tumours have devastating effects on the quality of life of the survivors, causing a high burden to families, carers and social services. Often, these patients encounter difficulties in employment and being active community members. My research aims to understand better the basic biology underlying how these human conditions arise, with the ultimate goal of developing safer and better treatments. The pituitary gland contains stem cells which give rise to new hormone-producing cells throughout life. However, how these cells are involved in the continuing function of the gland and the molecules controlling cell specification remain unknown. My research has demonstrated that WNT signalling factors, an essential group of proteins orchestrating normal development, play a role in the regulation of the pituitary stem cell compartment. This proposal aims to gain insights into stem cell biology using the pituitary gland as a model. Combining mouse genetics with live imaging of this organ, we will reveal how pituitary stem cells function and how WNT signalling is involved in regulating cell decisions by providing instructive cues. As the WNT pathway is closely linked to stem cell involvement in numerous human tumours and cancers, my research will have an important impact on elucidating the different roles of stem cells that could contribute to these conditions. This work will benefit the scientific community by providing advances in stem cell biology, which can in turn lead to better disease management and treatments for devastating human disorders.