Thyroid Follicular Cell Development in Mice and Humans

 描述(申请人提供)：甲状腺激素是胎儿发育的关键媒介，对成年后的正常新陈代谢和神经功能至关重要。它的合成由甲状腺控制，发育过程始于哺乳动物的胚胎发育。对这一过程和涉及的步骤的理解将对我们理解先天性甲状腺功能减退症产生深远的影响，先天性甲状腺功能减退症发生在4000名新生儿中，此外还将对人类甲状腺功能减退症的潜在细胞治疗产生深远的影响。此外，功能性甲状腺滤泡细胞在不同发育阶段的发育将为了解包括甲状腺癌和甲状腺激素合成缺陷在内的众多疾病提供一个理想的模型系统。重要的是，我们已经开发了一种独特的培养系统，可以从小鼠胚胎干细胞中开发出具有功能的甲状腺滤泡细胞，而不需要依赖于转录因子的强制过表达。重要的是，所涉及的信号通路在非洲爪哇和人类甲状腺发育中似乎是保守的。因此，我们现在可以机械地证明这一过程，并最终确定其在人类细胞中的功能。为了实现这一目标，我们提出了三个目标。在第一个目标中，我们将评估我们已经确定的两个关键信号通路在小鼠滤泡细胞发育中的作用，以确保我们开发的分化程序与内源性甲状腺发育平行。在第二个目标中，我们将利用我们的小鼠培养系统，开发将人类诱导的多能干细胞转化为甲状腺滤泡细胞的技术。最后，在目标3中，我们将使用基因编辑来修复导致先天性甲状腺功能减退的人类突变，并证明这种修复允许正常的甲状腺滤泡发育。这些目标的共同完成将提供对甲状腺如何发育和功能的关键洞察，并允许细胞疗法治疗甲状腺疾病的潜力。

 DESCRIPTION (provided by applicant): Thyroid hormone is a critical mediator of fetal development and then essential for normal metabolic and neurologic function during adulthood. Its synthesis by the thyroid is governed by a developmental process that begins during embryogenesis in mammals. An understanding of this process and the steps involved would have profound effects on our understanding of congenital hypothyroidism which occurs in 1/4000 births and additionally on potential cellular therapy for hypothyroidism in humans. Additionally, the development of functional thyroid follicular cells at different stages of development would provide an ideal model system to understand numerous diseases including thyroid cancer and defects in thyroid hormone synthesis. Importantly, we have developed a unique culture system to develop functioning thyroid follicular cells from mouse embryonic stem cells that does not rely on the forced overexpression of transcription factors. Importantly, the signaling pathways involved appear to be conserved in Xenopus and human thyroid development. Thus, we are now in position to mechanistically prove the process and finalize its function in human cells. To accomplish this we propose three Aims. In the first Aim, we will assess the role of two key signaling pathways we have identified in murine follicular cell development to ensure that differentiation program we have developed parallels endogenous thyroid development. In the second Aim, we will leverage our mouse culture system and develop technology to transform human induced pluripotent stem cells into thyroid follicular cells. Finally, in Aim 3 we will use genetic-editing to repair human mutations that cause congenital hypothyroidism and demonstrate that this repair allows for normal thyroid follicular development. Together completion of these Aims will provide key insight into how the thyroid develops and functions and allow for the potential of cellular therapies to treat thyroid disease.