Thyroid Follicular Cell Development in Mice and Humans

小鼠和人类甲状腺滤泡细胞的发育

基本信息

批准号：
9697589
负责人：
ANTHONY N HOLLENBERG
金额：
$ 18.9万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-13 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9697589
关键词：
Activities of Daily Living Adult Affect Alleles Area Attention Autologous Beta Cell Biological Models Birth Bone Morphogenetic Proteins Cell Therapy Cell model Cell physiology Cells Childhood Clone Cells Cretinism Defect Development Developmental Biology Developmental Process Disease Dose Down-Regulation Embryonic Development Endocrinology Ensure Epithelium Fetal Development Fibroblast Growth Factor Fluorochrome Future Gene Targeting Genes Genetic Genomics Health Human Human Development Hypothyroidism In Vitro Individual Insulin-Dependent Diabetes Mellitus Knowledge Lesion Life Lung Malignant neoplasm of thyroid Mammals Mediator of activation protein Metabolic Modeling Molecular Mus Mutation Nervous System Physiology Neurologic Pathway interactions Patients Positioning Attribute Process Replacement Therapy Reporter Role Signal Pathway Signal Transduction Stem Cell Development Stem cells System Technology Testing Therapeutic Uses Thyroid Diseases Thyroid Function Tests Thyroid Gland Thyroid Hormones Thyroxine Ursidae Family Work Xenopus base combinatorial design embryonic stem cell experimental study in vivo individualized medicine induced pluripotent stem cell insight mutant novel overexpression programs public health relevance repaired stem cell technology stem cell therapy therapy development transcription factor

项目摘要

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.

描述（由适用提供）：甲状腺马酮是胎儿发育的关键介体，然后在成年期对于正常的代谢和神经系统功能至关重要。甲状腺的合成由哺乳动物胚胎发生期间开始的发育过程控制。对这一过程和所涉及的步骤的理解将对我们对先天性甲状腺功能减退症的理解产生深远的影响，该甲状腺功能减退症发生在1/4000出生中，以及对人类甲状腺功能减退症的潜在细胞治疗。此外，在不同发育阶段，功能性甲状腺卵泡细胞的发育将提供理想的模型系统，以了解众多疾病，包括甲状腺癌和甲状腺雌雄同体合成中的缺陷。重要的是，我们开发了一种独特的培养系统，以从小鼠胚胎干细胞中开发出功能的甲状腺卵泡细胞，该细胞不依赖于转录因子的强制过表达。重要的是，涉及的信号通路似乎是在爪蟾和人甲状腺发育中配置的。那就是我们现在可以机械证明该过程并确定其在人类细胞中的功能。为此，我们提出了三个目标。在第一个目标中，我们将评估我们在鼠卵泡细胞发育中确定的两个关键信号通路的作用，以确保我们已经开发出内源性甲状腺发育的分化程序。在第二个目标中，我们将利用小鼠培养系统和开发技术将人类诱导的多能干细胞转化为甲状腺卵泡细胞。最后，在目标3中，我们将使用遗传编辑来修复引起先天甲状腺功能减退症的人类突变，并证明这种修复允许正常的甲状腺卵泡发育。这些目标的完成共同完成将提供有关甲状腺发育和功能的关键见解，并允许细胞疗法治疗甲状腺疾病的潜力。