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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：
10435571
负责人：
ANTHONY N HOLLENBERG
金额：
$ 35.64万
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：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10435571
关键词：
Adult Affect Anterior Area Attention BMP4 Biological Assay Birth 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 Epithelial FGF2 gene Fetal Development Fibroblast Growth Factor Future Genes Genetic Processes Goals Health Hormone replacement therapy Human Human Biology Hypothyroidism Immunodeficient Mouse In Vitro Individual Lead Life Longevity Mediator of activation protein 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 base bone morphogenic protein cell replacement therapy cell type design directed differentiation embryonic stem cell experimental study gene network gene regulatory network human disease human model in utero in vivo in vivo regeneration induced pluripotent stem cell insight molecular phenotype mutant 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 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.

项目总结