Project 1: Brain steroid receptor coactivators and energy homeostasis
项目1:脑类固醇受体共激活剂和能量稳态
基本信息
- 批准号:10421282
- 负责人:
- 金额:$ 31.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAdipose tissueAge of OnsetAnimal ModelAnorexiaAttenuatedBiochemicalBody WeightBody mass indexBrainBrain regionCRISPR/Cas technologyCharacteristicsChildChronicClustered Regularly Interspaced Short Palindromic RepeatsCodeComplexCuesCultured CellsDNA Sequence AlterationDevelopmentDietDissociationEatingEnergy IntakeEnergy MetabolismEnsureEquilibriumEstrogen Receptor alphaFOXO1A geneFastingFatty acid glycerol estersFeeding behaviorsGenesGenetic TranscriptionGlucoseHigh Fat DietHomeostasisHourHumanHyperphagiaHypothalamic structureImpairmentIndividualInsulinKnock-in MouseLeptinLiverLocomotionMediatingMediator of activation proteinMetabolicMetabolismModelingMolecularMusMutant Strains MiceMutationNeuronsNuclear ReceptorsNutritionalObesityPPAR gammaPathway interactionsPeripheralPhasePropertyProteinsRegimenReservationsRoleSignal TransductionSignaling MoleculeStat3 proteinSteroid ReceptorsSystemTechnologyTestingThyroid Hormone ReceptorTimeTissuesUniversitiesWeight Gaincohortdiet-induced obesityenergy balanceexhibitionsfeedinginsulin sensitivitymetabolic phenotypemind controlmouse modelmutantnew therapeutic targetnovelnovel therapeuticsnuclear receptor coactivator 1obesity preventionobesity treatmentoverexpressionpreventprogramsresponsesevere early onset obesitytranscription factortranscriptome
项目摘要
Project 1 - Project Summary
Numerous nuclear receptors (NRs) or transcription factors (TFs) have been identified as important regulators of
body weight. However, anti-obesity regimens targeting these individual molecules alone are far from satisfying.
Coactivators interact with a broad range of NRs/TFs and may serve as master regulators that coordinate and
synergize actions of multiple metabolic signals. High levels of Steroid Receptor Coactivator-1 and -2 (SRC-1 and
SRC-2) are expressed in the hypothalamus, the key brain region controlling feeding and body weight balance.
The pilot observations led to a hypothesis that hypothalamic SRC-1 and SRC-2 coactivate STAT3 and FoxO1,
repectively, to provide coordinated control of energy metabolism. Aim 1 will determine whether hypothalamic
SRC-1 fine-tunes STAT3 transcription activity to mediate the anti-obesity effects of leptin. Mouse models lacking
or overexpressing SRC-1 only in leptin-responsive neurons have been generated. Metabolic parameters in
response to different diets or to leptin treatment will be assessed in these mice. Importantly, the molecular
mechanisms by which the SRC1-pSTAT3 complex regulates leptin signaling will be delineated. Aim 2 will
determine whether human SRC-1 mutations impair leptin-STAT3 pathway in the hypothalamus and cause
obesity. Using the CRISPR technology, a knockin mouse line has been generated to mimic a SRC-1 genetic
mutation associated with human obesity. Metabolic phenotypes of these mice will be characterized, and leptin-
STAT3 actions and STAT3 transcription activity will be evaluated. Aim 3 will determine whether hypothalamic
SRC-2 coativates FoxO1 transcriptional activity to facilitate energy reservations. Mice lacking or overexpressing
SRC-2 in mature POMC neurons have been generated, with/without FoxO1 overexpression. Metabolic
phenotypes will be characterized in all these models and FoxO1 transcriptional activity will also be evaluated.
项目1--项目项目摘要:
--
许多核受体(NRs)或转录因子(TF)已被确定为全球最重要的监管机构。
体重。然而,仅针对这些个体健康分子的抗肥胖治疗方案远远不能令人满意。
共同激活者与范围广泛的一系列NRS/TF进行互动,他们可能还会作为主要的监管机构,负责协调他们和他们的关系。
协同多种代谢信号的作用。高水平的类固醇激素受体和辅活化子-1和辅活化子-2(SRC--1)和。
这些基因在下丘脑表达,下丘脑是控制进食和体重平衡的关键脑区。
飞行员的观察结果导致他们提出了一个新的假设,即下丘脑SRC-1和SRC-2共同激活STAT3和FoxO1,。
对此,我们的目标是为能量和新陈代谢提供一个协调的控制系统。这一目标将不会决定是否有下丘脑功能障碍。
SRC-1微调STAT3基因转录活性,以进一步调节瘦素的抗肥胖效应。小鼠模型缺乏。
或者,SRC-1的过度表达只在瘦素反应的神经元中存在,这些神经元还没有生成。
对不同饮食或瘦素治疗方案的反应将不会在这些小鼠身上进行评估。更重要的是,他们的分子水平。
将不会详细描述由SRC1--pSTAT3组成的复合体调节瘦素信号传导的机制。
确定人类SRC-1基因突变是否会损害下丘脑中瘦素-STAT3途径的表达,并导致这种情况。
肥胖。由于使用了最新的CRISPR基因技术,已经成功地产生了一种新的敲击小鼠品系的基因,以模仿一种新的SRC-1基因。
突变与人类肥胖有关。这些突变小鼠的代谢和表型将不会被描述为新的特征,包括瘦素-1。
STAT3的行动和STAT3的转录活性将不会被评估。STAT3的目标将不会决定是否会影响下丘脑。
SRC--2使FoxO1的转录调节活性降低,以进一步促进能量储备。小鼠缺乏表达或过度表达。
在成熟的POMC中,SRC-2的神经元尚未生成,但有/没有FoxO1基因的过度表达。
表型也将在所有这些模型中得到表征,FoxO1的转录活性也将得到进一步评估。
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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YONG XU其他文献
Synthesis of molybdenum disulfide from waste Mo materials
废钼原料合成二硫化钼
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
YONG -KUI CAI;YONG XU;XIAO -QIANG WANG;KUN -HONG HU - 通讯作者:
KUN -HONG HU
YONG XU的其他文献
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{{ truncateString('YONG XU', 18)}}的其他基金
Brain Estrogen Regulates Energy and Glucose Balance
大脑雌激素调节能量和血糖平衡
- 批准号:
10032667 - 财政年份:2020
- 资助金额:
$ 31.7万 - 项目类别:
Brain Estrogen Regulates Energy and Glucose Balance
大脑雌激素调节能量和血糖平衡
- 批准号:
10443842 - 财政年份:2020
- 资助金额:
$ 31.7万 - 项目类别:
Brain Estrogen Regulates Energy and Glucose Balance
大脑雌激素调节能量和血糖平衡
- 批准号:
10654694 - 财政年份:2020
- 资助金额:
$ 31.7万 - 项目类别:
Brain Estrogen Regulates Energy and Glucose Balance
大脑雌激素调节能量和血糖平衡
- 批准号:
10256073 - 财政年份:2020
- 资助金额:
$ 31.7万 - 项目类别:
Neurobiology for the sex differences in energy balance
能量平衡性别差异的神经生物学
- 批准号:
9901528 - 财政年份:2018
- 资助金额:
$ 31.7万 - 项目类别:
Neurobiology for the sex differences in energy balance
能量平衡性别差异的神经生物学
- 批准号:
10374807 - 财政年份:2018
- 资助金额:
$ 31.7万 - 项目类别:
Project 1: Brain steroid receptor coactivators and energy homeostasis
项目1:脑类固醇受体共激活剂和能量稳态
- 批准号:
10153760 - 财政年份:2018
- 资助金额:
$ 31.7万 - 项目类别:
Targeting hypothalamic steroid receptor co-activator-1 to treat obesity
靶向下丘脑类固醇受体辅激活剂-1 治疗肥胖
- 批准号:
8921991 - 财政年份:2014
- 资助金额:
$ 31.7万 - 项目类别:
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