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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：
9902423
负责人：
ANTHONY N HOLLENBERG
金额：
$ 68.27万
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/9902423
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 Diet 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 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 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.

项目总结