Thyroid Hormone Signaling in Human Hepatocytes
Thyroid Hormone Signaling in Human Hepatocytes
批准号:
10337213
负责人:
ANTHONY N HOLLENBERG
金额:
$30.64万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-04-01 至 2022-11-14
关键词:
AdultAffectBinding ProteinsBiological ModelsBody WeightCRISPR interferenceCRISPR/Cas technologyCarbohydratesCell LineCell modelCellsCholesterol HomeostasisClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCoupledDataDefectDerivation procedureDevelopmentDiagnosisDiseaseDisease modelElementsFailureFatty AcidsFetal DevelopmentGenesGenetic 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
中文摘要
项目摘要
甲状腺激素是成年期发育和生理功能的重要调节因子。它的作用是
每种细胞类型都通过基因组和非基因组机制,但尚未明确定义
在人类身上。我们对甲状腺激素作用的大部分洞察来自小鼠的遗传模型
在保护下丘脑-垂体甲状腺轴的情况下,似乎模拟了人类的生理学。在……里面
此外,人类的疾病,如对甲状腺激素的抗药性,已经证实了老鼠的使用
模型,但主要问题仍然是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极其有限,因为缺乏
对甲状腺激素有反应。绕过这一点并开始了解甲状腺激素的作用
人类我们已经从诱导的多能干细胞(IPSCs)中培育出了人类肝细胞
反应灵敏。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,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
在参与生理途径和参与基因组靶标的背景下,都存在异构体。在第二个
目的我们将使用我们的人肝细胞模型和小鼠遗传模型来了解
甲状腺激素信号在代谢肝病应对饮食挑战的调节中的作用。
最后,在第三个目标中,我们将使用CRISPR-Cas9系统来建立人类疾病模型
甲状腺激素信号,既可以识别新的治疗途径,也可以帮助理解
这种表型存在于患者身上。这些目标的共同完成将提供对如何
人类细胞中的甲状腺激素信号不仅在正常生理背景下,而且在疾病状态和
开辟新的途径,针对这些途径治疗代谢性疾病。
英文摘要
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.
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会议论文
Thyroid Hormone Signaling in Human Hepatocytes
-
批准号:10874207
-
项目类别:
-
资助金额:$33.63万
-
财政年份:2023
-
负责人:ANTHONY N HOLLENBERG
-
依托单位:
Thyroid Follicular Cell Signaling and Development in Humans
-
批准号:10801642
-
项目类别:
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资助金额:$41.25万
-
财政年份:2023
-
负责人:ANTHONY N HOLLENBERG
-
依托单位:
Hypothalamic regulation by thyroid hormone receptor phosphorylation
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批准号:10717820
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项目类别:
-
资助金额:$0.0万
-
财政年份:2023
-
负责人:ANTHONY N HOLLENBERG
-
依托单位:
Corepressor regulation of nuclear receptor action
-
批准号:10562608
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项目类别:
-
资助金额:$13.22万
-
财政年份:2022
-
负责人:ANTHONY N HOLLENBERG
-
依托单位:
Thyroid Hormone Signaling in Human Hepatocytes
-
批准号:9902423
-
项目类别:
-
资助金额:$68.27万
-
财政年份:2019
-
负责人:ANTHONY N HOLLENBERG
-
依托单位:
Thyroid Hormone Signaling in Human Hepatocytes
-
批准号:10087920
-
项目类别:
-
资助金额:$65.86万
-
财政年份:2019
-
负责人:ANTHONY N HOLLENBERG
-
依托单位:
Corepressor regulation of nuclear receptor action
-
批准号:9701510
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项目类别:
-
资助金额:$66.99万
-
财政年份:2018
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负责人:ANTHONY N HOLLENBERG
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依托单位:
Thyroid Follicular Cell Development in Mice and Humans
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批准号:9697589
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项目类别:
-
资助金额:$18.9万
-
财政年份:2018
-
负责人:ANTHONY N HOLLENBERG
-
依托单位:
Thyroid Follicular Cell Signaling and Development in Humans
-
批准号:10435571
-
项目类别:
-
资助金额:$35.64万
-
财政年份:2015
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负责人:ANTHONY N HOLLENBERG
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依托单位:
Thyroid Follicular Cell Development in Mice and Humans
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批准号:9035478
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项目类别:
-
资助金额:$39.66万
-
财政年份:2015
-
负责人:ANTHONY N HOLLENBERG
-
依托单位:
Thyroid Follicular Cell Signaling and Development in Humans
-
批准号:10298043
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项目类别:
-
资助金额:$37.11万
-
财政年份:2015
-
负责人:ANTHONY N HOLLENBERG
-
依托单位:
New Targets of Thyroid Hormone Action
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批准号:8900278
-
项目类别:
-
资助金额:$50.64万
-
财政年份:2013
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负责人:ANTHONY N HOLLENBERG
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依托单位:
New Targets of Thyroid Hormone Action
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批准号:9090055
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项目类别:
-
资助金额:$50.64万
-
财政年份:2013
-
负责人:ANTHONY N HOLLENBERG
-
依托单位:
New Targets of Thyroid Hormone Action
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批准号:8735134
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项目类别:
-
资助金额:$50.64万
-
财政年份:2013
-
负责人:ANTHONY N HOLLENBERG
-
依托单位:
New Targets of Thyroid Hormone Action
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批准号:8630009
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项目类别:
-
资助金额:$53.34万
-
财政年份:2013
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负责人:ANTHONY N HOLLENBERG
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依托单位:
Defining the thyroid hormone receptor Cistrome in vivo
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批准号:8299630
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项目类别:
-
资助金额:$21.75万
-
财政年份:2011
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负责人:ANTHONY N HOLLENBERG
-
依托单位:
Defining the thyroid hormone receptor Cistrome in vivo
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批准号:8114945
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项目类别:
-
资助金额:$26.1万
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财政年份:2011
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负责人:ANTHONY N HOLLENBERG
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依托单位:
Negative regulation by thyroid hormone
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批准号:8009199
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项目类别:
-
资助金额:$5.09万
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财政年份:2010
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负责人:ANTHONY N HOLLENBERG
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依托单位:
Negative regulation by thyroid hormone
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批准号:7585204
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项目类别:
-
资助金额:$33.32万
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财政年份:2007
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负责人:ANTHONY N HOLLENBERG
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依托单位:
Negative regulation by thyroid hormone
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批准号:7247441
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项目类别:
-
资助金额:$34.0万
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财政年份:2007
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负责人:ANTHONY N HOLLENBERG
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依托单位:
海外基金