Function and Regulation of the Pituitary Stem Cell Compartment in Mammals

脑下垂体是生理过程如新陈代谢、生殖、生长和应激反应的中心调节器。垂体前叶负责六种激素的持续生产，当负责其生产的专门细胞群耗尽或受损时，激素水平可能会不足，这种情况称为垂体功能减退症。这种情况影响高达1/4000的个体，并与相当大的发病率和死亡率相关。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茁壮成长或无法进入青春期，这是由缺乏促性腺激素引起的。类似地，脑下垂体中细胞的过度增殖导致肿瘤，这反过来会损害健康的脑下垂体组织，导致脑下垂体功能减退，这也可以从手术和治疗期间的损伤中发展出来。这些肿瘤大多数对幸存者的生活质量产生破坏性影响，给家庭、照顾者和社会服务造成沉重负担。这些病人往往在就业和成为社区积极成员方面遇到困难。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，这些干细胞在整个生命过程中产生新的分泌细胞。然而，这些细胞如何参与腺体的持续功能以及控制细胞特化的分子仍然未知。我的研究已经证明，WNT信号传导因子，一组重要的蛋白质协调正常的发展，发挥作用，在调节垂体干细胞室。该提案旨在以脑下垂体为模型深入了解干细胞生物学。将小鼠遗传学与该器官的实时成像相结合，我们将揭示垂体干细胞的功能以及WNT信号传导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。这项工作将通过提供干细胞生物学的进步而使科学界受益，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.