Function and Regulation of the Pituitary Stem Cell Compartment in Mammals

脑下垂体是新陈代谢、生殖、生长和应激反应等生理过程的中心调节器。脑垂体前叶负责持续产生六种荷尔蒙，当负责产生荷尔蒙的特殊细胞群耗尽或受损时，荷尔蒙水平可能会变得不足，这种情况被称为垂体功能减退。这种情况影响高达4000人中的1人，并与相当大的发病率和死亡率有关。已知的例子是遗传性侏儒症，由于缺乏生长激素导致儿童无法发育或无法进入青春期，这是由于缺乏促性腺激素造成的。同样，脑下垂体细胞的过度增殖会导致肿瘤，而肿瘤又会损害健康的脑下垂体组织，导致垂体功能减退，这种情况也可能在手术和治疗过程中受到损害而发展起来。这些肿瘤大多对幸存者的生活质量造成破坏性影响，给家庭、照顾者和社会服务造成沉重负担。这些患者往往在就业和成为活跃的社区成员方面遇到困难。我的研究旨在更好地了解这些人类疾病发生的基本生物学基础，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，可以在一生中产生新的荷尔蒙分泌细胞。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不清楚。我的研究表明，WNT信号因子是协调正常发育的一组必不可少的蛋白质，在调节脑下垂体干细胞隔室中发挥着作用。这项建议旨在以脑下垂体为模型，深入了解干细胞生物学。结合小鼠遗传学和对这个器官的实时成像，我们将揭示垂体干细胞是如何发挥作用的，以及WNT信号是如何通过提供有益的线索参与调节细胞决定的。由于WNT途径与干细胞在许多人类肿瘤和癌症中的参与密切相关，我的研究将对阐明可能导致这些疾病的干细胞的不同角色产生重要影响。这项工作将通过提供干细胞生物学方面的进展而使科学界受益，干细胞生物学反过来可以带来更好的疾病管理和对毁灭性人类疾病的治疗。

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.