Thyroid Follicular Cell Development in Mice and Humans

小鼠和人类甲状腺滤泡细胞的发育

• 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
• 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

 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.