Thyroid Follicular Cell Signaling and Development in Humans

人类甲状腺滤泡细胞信号传导和发育

基本信息

批准号：
10801642
负责人：
ANTHONY N HOLLENBERG
金额：
$ 41.25万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10801642
关键词：
Adult Affect Anterior Area Attention BMP4 Biological Assay Birth Bone Morphogenetic Proteins Cell Line Cell Lineage Cell Therapy Cell Transplantation Cells Clone Cells Computer Models Cretinism DNA Sequence Alteration Defect Derivation procedure Development Developmental Biology Endoderm Engineering Ensure Epithelium Experimental Designs FGF2 gene Fetal Development Fibroblast Growth Factor Future Genes Genetic Processes Goals Growth Factor Health Heterozygote Hormone replacement therapy Hormone secretion Human Human Biology Hypothyroidism Immunodeficient Mouse Immunologic Deficiency Syndromes In Vitro Individual Lead Life Longevity Mediator Methodology Modeling Mus Mutation Natural regeneration Organoids Pathway interactions Patients Pluripotent Stem Cells Population Primitive foregut structure Process Production Quantitative Evaluations Rana Regenerative capacity Reporter Resolution Role Safety Signal Transduction Testing Therapeutic Thyroid Diseases Thyroid Function Tests Thyroid Gland Thyroid Hormones Thyroxine Tissues Transplantation Work cell replacement therapy cell type directed differentiation embryonic stem cell gene network gene regulatory network human disease human model in utero in vivo in vivo regeneration induced pluripotent stem cell insight molecular phenotype mutant mutation correction novel overexpression pre-clinical preclinical development progenitor reconstitution regenerative cell regenerative therapy single-cell RNA sequencing stem cell based approach stem cell technology stem cells success transcription factor volunteer

项目摘要

Project Summary The development of the thyroid gland from anterior endoderm is an essential step in development that allows for the production of thyroid hormones around week 12 in utero in humans. Unfortunately, in about 1/4000 births genetic mutations that affect this development pathway lead to congenital hypothyroidism requiring lifelong thyroid hormone replacement therapy. Thus, a better understanding of thyroid follicular cell development could lead to a process where genetic editing and cellular therapy could provide treatment for congenital hypothyroidism (CH). Our work in this area has utilized a directed differentiation approach and has identified bone morphogenic protein and fibroblast growth factor as key mediators of thyroid follicular cell lineage development across species resulting in functional murine thyroid follicular cells that can rescue athyreotic mice. In this proposal, we now turn our attention exclusively to human thyroid follicular cell development and propose three Specific Aims that will allow for the pre-clinical development of functioning human thyroid follicular cells derived from human induced pluripotent stem cells (iPSCs), In the first Aim we will utilize a novel lineage tracing methodology to understand how developing human thyroid follicular acquire their cell fate and to ensure that the process in iPSC parallels that in vivo. In the second Aim we will prove that the human thyroid follicular cells derived from iPSCs are fully able to produce thyroid hormones in vitro and can be transplanted into immunodeficient athyreotic mice to rescue their hypothyroidism. Finally, in the third Aim we will demonstrate pre- clinically that derived iPSCs from a patient with CH can be genetically corrected and re-introduced via transplant to function normally. Together completion of these Aims will provide key insight into the possibilities of iPSC derived cellular therapy for the treatment of CH and enhance our understanding of the development endodermal- derived tissues in humans.

项目概要甲状腺从前内胚层发育是发育的一个重要步骤，它允许人类在子宫内第 12 周左右就会产生甲状腺激素。不幸的是，大约 1/4000 的新生儿影响这一发育途径的基因突变会导致先天性甲状腺功能减退症，需要终身治疗甲状腺激素替代疗法。因此，更好地了解甲状腺滤泡细胞的发育可以导致基因编辑和细胞疗法可以为先天性疾病提供治疗的过程甲状腺功能减退症（CH）。我们在这一领域的工作采用了定向差异化方法，并确定了骨形态发生蛋白和成纤维细胞生长因子作为甲状腺滤泡细胞谱系的关键介质跨物种发育产生功能性小鼠甲状腺滤泡细胞，可以拯救患有甲状腺疾病的小鼠。在这项提案中，我们现在将注意力集中在人类甲状腺滤泡细胞的发育上，并提出三个具体目标将允许功能性人类甲状腺滤泡细胞的临床前开发源自人类诱导多能干细胞 (iPSC)，第一个目标是我们将利用一种新颖的谱系追踪技术方法来了解发育中的人类甲状腺滤泡如何获得其细胞命运并确保 iPSC 中的过程与体内的过程相似。在第二个目标中，我们将证明人类甲状腺滤泡细胞来自 iPSC 的细胞完全能够在体外产生甲状腺激素，并且可以移植到体内免疫缺陷的甲状腺小鼠以挽救其甲状腺功能减退症。最后，在第三个目标中，我们将演示预临床上，来自 CH 患者的 iPSC 可以进行基因纠正并通过移植重新引入才能正常运作。这些目标的共同完成将为 iPSC 的可能性提供重要的见解衍生细胞疗法治疗 CH 并增强我们对内胚层发育的了解人体的衍生组织。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regenerative therapy for hypothyroidism: Mechanisms and possibilities.

DOI：
10.1016/j.mce.2016.11.012
发表时间：
2017-04-15
期刊：
Molecular and cellular endocrinology
影响因子：
4.1
作者：
Hollenberg AN;Choi J;Serra M;Kotton DN
通讯作者：
Kotton DN

Editorial: Progenitors and Stem Cells in Thyroid Development, Disease, and Regeneration.

DOI：
10.3389/fendo.2022.848559
发表时间：
2022
期刊：
Frontiers in endocrinology
影响因子：
5.2
作者：
Kotton DN;Nilsson M
通讯作者：
Nilsson M

Derivation of Thyroid Follicular Cells From Pluripotent Stem Cells: Insights From Development and Implications for Regenerative Medicine.

DOI：
10.3389/fendo.2021.666565
发表时间：
2021
期刊：
Frontiers in endocrinology
影响因子：
5.2
作者：
Posabella A;Alber AB;Undeutsch HJ;Droeser RA;Hollenberg AN;Ikonomou L;Kotton DN
通讯作者：
Kotton DN