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 -项目概要
许多核受体(NR)或转录因子(TF)已被鉴定为细胞增殖的重要调节因子。
然而,单独靶向这些单个分子的抗肥胖症方案远不能令人满意。
共激活因子与广泛的NR/TF相互作用,并且可以充当协调和调节细胞内的细胞因子的主调节因子。
高水平的类固醇受体辅激活因子-SRC-CRP 1和-SRC-CRP 2(SRC-CRP 1和SRC-CRP 2)可促进多种代谢信号的协同作用。
SRC-E2)在下丘脑中表达,下丘脑是控制进食和体重平衡的关键大脑区域。
初步观察导致了下丘脑SRC-B11和SRC-B12共激活STAT 3和FoxO 1的假设,
分别提供协调控制的能量代谢。目标1将确定是否下丘脑
SRC-STAT 1精细调节STAT 3转录活性以介导瘦素的抗肥胖作用。
或仅在瘦素-β 1反应性神经元中过表达SRC-B1。
将在这些小鼠中评估对不同饮食或对瘦素治疗的反应。
SRC 1-pSTAT 3复合物调节瘦素信号传导的机制将被阐明。
确定人类SRC-STAT 1突变是否损害下丘脑中的瘦素-STAT 3通路,
使用CRISPR技术,已经产生了敲入小鼠系,以模拟SRC-CRIS 1基因。
这些小鼠的代谢表型将被表征,并且瘦素-β 2受体将被检测。
目的3:研究STAT 3的作用和转录活性。
SRC-RX 2共激活FoxO 1转录活性以促进能量储备。
在有/没有FoxO 1过表达的情况下,已经在成熟POMC神经元中产生了SRC-B12。
表型将在所有这些模型中表征,并且FoxO 1转录活性也将被评估。
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:
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:
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:
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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