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

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

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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.

项目摘要甲状腺激素是成年期发育和生理功能的关键介体。它起作用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见解来自小鼠遗传模型考虑到下丘脑垂体甲状腺轴的保存，似乎模仿了人类生理。在此外，人类疾病，例如对甲状腺激素的抗性，已验证了小鼠的使用模型但主要的问题仍然存在于细胞特异性和可能发生的独特范例的背景下人类细胞类型。由于缺乏模型，在人类系统中的工作非常有限甲状腺激素反应能力。要解决这个问题，并开始理解甲状腺激素动作人类我们已经从诱导的多能干细胞（IPSC）中发展了人类肝细胞高度反应。此外，使用这种独特的模型和基因编辑技术，我们也可以在细胞水平上建模人类疾病。为了进一步了解人类甲状腺激素作用，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同工型在参与生理途径和参与基因组靶标的背景下。在第二个目的，我们将使用人类肝细胞模型以及小鼠遗传模型来了解甲状腺激素信号在响应饮食挑战时调节代谢性肝病的调节。最后，在第三个目标中，我们将使用CRISPR-CAS9系统开发人类疾病模型甲状腺激素信号传导，既识别新型的治疗途径，又有助于理解患者存在的表型。这些目标共同完成将提供有关如何的关键见解在正常生理的背景下，疾病状态和开辟新的途径，以这些途径为目标，以治疗代谢疾病。