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:
- 金额:$ 65.86万
- 依托单位:
- 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:
- 关键词:AdultAffectBinding ProteinsBiological ModelsBody WeightCRISPR interferenceCRISPR/Cas technologyCarbohydratesCell LineCell modelCellsCholesterol HomeostasisClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCoupledDataDefectDerivation procedureDevelopmentDiagnosisDiseaseDisease modelElementsFailureFatty AcidsFetal DevelopmentGap JunctionsGenesGenetic ModelsGenomicsGluconeogenesisHealthHepatocyteHormone ResponsiveHumanHyperthyroidismLeadLightLiverLiver diseasesMediator of activation proteinMetabolicMetabolic DiseasesMetabolic PathwayMetabolismModelingMolecularMutationPathway AnalysisPathway interactionsPatientsPharmaceutical PreparationsPhenotypePhysiologicalPhysiologyPopulationProtein IsoformsRare DiseasesRegulationResistanceRoleSignal TransductionSpecificityStressSystemTechniquesTechnologyTestingThyroid Hormone ReceptorThyroid HormonesTissuesWorkanalogcell typeclinical phenotypedietaryembryonic stem cellgenome editingglucose metabolismhormonal signalshormone analoghuman diseasehuman modelhuman tissuehypothalamic-pituitary-thyroid axisinduced pluripotent stem cellinduced pluripotent stem cell technologyinsightinsulin sensitivityknock-downlipid biosynthesislipid metabolismliver metabolismmouse geneticsmouse modelmutantnon-genomicnovelnovel therapeuticsnuclear receptor coactivator 1responsesmall moleculestem cell technologytranslational 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.
项目摘要
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
每种细胞类型通过基因组和非基因组机制,尚未明确定义
在人类身上。我们对甲状腺激素作用的许多认识来自小鼠遗传模型,
考虑到下丘脑-垂体-甲状腺轴的保守性,似乎模仿人类生理学。在
此外,人类疾病,如对甲状腺激素的抵抗,已经证实了使用小鼠
模型,但主要问题仍然是在细胞特异性和独特的范式,可能发生在
人类细胞类型。人类系统中的工作一直非常有限,因为缺乏模型,
对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在
我们已经从诱导多能干细胞(iPSC)中开发了人类肝细胞,
高度响应。此外,使用这种独特的模型和基因编辑技术,我们还可以
在细胞水平上模拟人类疾病。为了进一步了解人类甲状腺激素的作用,
提出三个具体目标。在第一个目的中,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,在第二
目的我们将使用我们的人肝细胞模型沿着小鼠遗传模型来理解
甲状腺激素信号在代谢性肝病的调节中对饮食挑战的反应。
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,既确定新的治疗途径,也有助于了解
患者中存在的表型。这些目标的共同完成将提供关键的洞察力,
甲状腺激素信号在人体细胞中,无论是在正常的生理环境中,还是在疾病状态中,
开辟了新的途径,在代谢疾病的治疗中靶向这些途径。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ANTHONY N HOLLENBERG其他文献
ANTHONY N HOLLENBERG的其他文献
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{{ truncateString('ANTHONY N HOLLENBERG', 18)}}的其他基金
Thyroid Hormone Signaling in Human Hepatocytes
人肝细胞中的甲状腺激素信号传导
- 批准号:
10874207 - 财政年份:2023
- 资助金额:
$ 65.86万 - 项目类别:
Thyroid Follicular Cell Signaling and Development in Humans
人类甲状腺滤泡细胞信号传导和发育
- 批准号:
10801642 - 财政年份:2023
- 资助金额:
$ 65.86万 - 项目类别:
Hypothalamic regulation by thyroid hormone receptor phosphorylation
甲状腺激素受体磷酸化对下丘脑的调节
- 批准号:
10717820 - 财政年份:2023
- 资助金额:
$ 65.86万 - 项目类别:
Corepressor regulation of nuclear receptor action
核受体作用的辅阻遏物调节
- 批准号:
10562608 - 财政年份:2022
- 资助金额:
$ 65.86万 - 项目类别:
Thyroid Hormone Signaling in Human Hepatocytes
人肝细胞中的甲状腺激素信号传导
- 批准号:
9902423 - 财政年份:2019
- 资助金额:
$ 65.86万 - 项目类别:
Thyroid Hormone Signaling in Human Hepatocytes
人肝细胞中的甲状腺激素信号传导
- 批准号:
10337213 - 财政年份:2019
- 资助金额:
$ 65.86万 - 项目类别:
Corepressor regulation of nuclear receptor action
核受体作用的辅阻遏物调节
- 批准号:
9701510 - 财政年份:2018
- 资助金额:
$ 65.86万 - 项目类别:
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 - 财政年份:2018
- 资助金额:
$ 65.86万 - 项目类别:
Thyroid Follicular Cell Signaling and Development in Humans
人类甲状腺滤泡细胞信号传导和发育
- 批准号:
10435571 - 财政年份:2015
- 资助金额:
$ 65.86万 - 项目类别:
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:
9035478 - 财政年份:2015
- 资助金额:
$ 65.86万 - 项目类别:
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