Thyroid Hormone Signaling in Human Hepatocytes

人肝细胞中的甲状腺激素信号传导

基本信息

批准号：
10087920
负责人：
ANTHONY N HOLLENBERG
金额：
$ 65.86万
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：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10087920
关键词：
Adult Affect Binding Proteins Biological Models Body Weight CRISPR interference CRISPR/Cas technology Carbohydrates Cell Line Cell model Cells Cholesterol Homeostasis Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Coupled Data Defect Derivation procedure Development Diagnosis Disease Disease model Elements Failure Fatty Acids Fetal Development Gap Junctions Genes Genetic Models Genomics Gluconeogenesis Health Hepatocyte Hormone Responsive Human Hyperthyroidism Lead Light Liver Liver diseases Mediator of activation protein Metabolic Metabolic Diseases Metabolic Pathway Metabolism Modeling Molecular Mutation Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiological Physiology Population Protein Isoforms Rare Diseases Regulation Resistance Role Signal Transduction Specificity Stress System Techniques Technology Testing Thyroid Hormone Receptor Thyroid Hormones Tissues Work analog cell type clinical phenotype dietary embryonic stem cell genome editing glucose metabolism hormonal signals hormone analog human disease human model human tissue hypothalamic-pituitary-thyroid axis induced pluripotent stem cell induced pluripotent stem cell technology insight insulin sensitivity knock-down lipid biosynthesis lipid metabolism liver metabolism mouse genetics mouse model mutant non-genomic novel novel therapeutics nuclear receptor coactivator 1 response small molecule stem cell technology translational study

项目摘要

Project Summary Thyroid hormone is a critical mediator of development and physiologic function in adulthood. It acts on every cell type through both genomic and non-genomic mechanisms that have not been clearly defined in humans. Much of our insight into thyroid hormone action comes from mouse genetic models which appear to mimic human physiology given the conservation of the hypothalamic-pituitary thyroid axis. In addition, human diseases, such as resistance to thyroid hormone, have validated the use of mouse models but major question remain in context of cell specificity and unique paradigms that may occur in human cell types. Work in human systems has been extremely limited because of the lack of models that are thyroid hormone responsive. To get around this and begin to understand thyroid hormone action in humans we have developed human hepatocytes from induced pluripotent stem cells (iPSCs) that are highly TH responsive. Furthermore, using this unique model and gene editing techniques we can also model human disease at the cellular level. To gain further insight into human thyroid hormone action we propose three specific aims. In the first Aim we will determine the role of thyroid hormone receptor isoforms both in context of physiologic pathways engaged and genomic targets engaged. In the second Aim we will use our human hepatocyte model along with mouse genetic models to understand the role of thyroid hormone signaling in the regulation of metabolic liver disease in response to dietary challenges. Finally, in the third Aim we will use the CRISPR-Cas9 system to develop human disease models of thyroid hormone signaling, to both identify novel therapeutic pathways but also to aid in understanding the phenotype present in patients. Together completion of these Aims will provide key insight into how thyroid hormone signal in human cells both in context of normal physiology but also in disease states and open up new avenues to target these pathways in the treatment of metabolic disease.

项目概要甲状腺激素是成年期发育和生理功能的关键介质。它作用于通过尚未明确定义的基因组和非基因组机制的每种细胞类型在人类中。我们对甲状腺激素作用的大部分了解来自小鼠遗传模型，鉴于下丘脑-垂体甲状腺轴的保护，似乎模仿了人类生理学。在此外，人类疾病，例如甲状腺激素抵抗，已经验证了小鼠的使用模型，但主要问题仍然是细胞特异性和可能出现的独特范式的背景人类细胞类型。由于缺乏模型，人类系统中的工作极其有限。甲状腺激素有反应。为了解决这个问题并开始了解甲状腺激素的作用我们已经从诱导多能干细胞 (iPSC) 中培育出人类肝细胞，这些细胞是高度 TH 响应。此外，利用这种独特的模型和基因编辑技术，我们还可以在细胞水平上建立人类疾病模型。为了进一步了解人类甲状腺激素的作用，我们提出三个具体目标。在第一个目标中，我们将确定甲状腺激素受体的作用在参与的生理途径和参与的基因组靶标的背景下的亚型。在第二个我们的目标是使用人类肝细胞模型和小鼠遗传模型来了解甲状腺激素信号传导调节代谢性肝病以应对饮食挑战。最后，在第三个目标中，我们将使用CRISPR-Cas9系统来开发人类疾病模型甲状腺激素信号传导，既可以识别新的治疗途径，也可以帮助理解患者中存在的表型。共同完成这些目标将为我们提供关键的见解人类细胞中的甲状腺激素信号不仅在正常生理情况下而且在疾病状态和开辟针对这些途径治疗代谢疾病的新途径。