Neuronal control of body weight and size by the Gbeta5-R7 signaling complex
Gbeta5-R7 信号复合物对体重和体型的神经元控制
基本信息
- 批准号:10001791
- 负责人:
- 金额:$ 19.19万
- 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:2019-09-15 至 2020-08-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAcuteAdultAffectAgonistAllelesAnimalsAntibodiesBehaviorBeta CellBiochemicalBiological AssayBiophysicsBody SizeBody WeightBrainCRISPR/Cas technologyCardiovascular DiseasesCardiovascular systemCell LineCell NucleusCellsComorbidityComplexControl AnimalDataDiabetes MellitusDiagnosticDiseaseEnergy IntakeEngineeringEtiologyEventFamilyG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGNB5 geneGTP-Binding Protein RegulatorsGTP-Binding Protein beta SubunitsGTP-Binding ProteinsGene TransferGenesGeneticGoalsGrowthHealthHormone secretionHormonesHumanHuman GeneticsHypothalamic HormonesHypothalamic structureImage AnalysisIn SituIn VitroInjectionsInsulinInvestigationKidney DiseasesKnock-outLeadLinkLoxP-flanked alleleMalignant NeoplasmsMeasurementMediatingMessenger RNAMetabolic DiseasesMetabolic syndromeMetabolismMethodsMicroscopicMolecularMusMuscarinic Acetylcholine ReceptorMutationNeuraxisNeuroendocrinologyNeurogliaNeurologicNeuronsNeurosciencesNeurosecretionNeurosecretory SystemsNeurotransmittersNon-Insulin-Dependent Diabetes MellitusObesityOrganPancreasPathologicPathway interactionsPatternPeripheralPharmacologyPhenotypePhosphorylationPhysiologicalPlayPopulationProteinsRGS ProteinsRegulationReproductionResearchRisk FactorsRoleSecond Messenger SystemsSerumSignal TransductionSignaling ProteinSliceStimulusStrokeStructureStructure of beta Cell of isletSystemTechnologyTestingTherapeuticTissuesUnited StatesViralViral VectorVirusWeight Gainbasecholinergicdesigndimereffective therapyexperimental studyhormonal signalshormone regulationimprovedin vivoinsightinsulin secretionkinase inhibitorknock-downknockout genemutantnervous system disordernoveloverexpressionpromoterprotein complexprotein functionprotein protein interactionreal-time images
项目摘要
Abstract
Obesity is a major co-morbidity factor in diabetes, cancer, cardiovascular, neurological and other
diseases. One group of genes recently linked to obesity in humans are genes encoding the R7 family of
regulator of G protein signaling proteins (RGS6, 7, 9 and 11) and Gnb5, which encodes the G protein beta
subunit G5. G5 and R7 proteins form obligatory dimers, so that the Gnb5 knockout causes complete
degradation of the entire G5-R7 complex. This proposal studies how a deficiency in the Gnb5 and R7 genes
can lead to obesity; the ultimate goal is to discover effective treatments of disorders associated with
neuroendocrine pathways regulated by these genes.
The proposed research plan builds upon earlier discoveries that together constitute a strong premise
for this study. Ablation of one Gnb5 allele leads to obesity and metabolic syndrome in mice; this finding was
later confirmed by human genetics. Subsequent mechanistic investigations in this lab identified a novel role for
the G5-R7 complex in pancreatic beta cells where G5-R7 strongly promoted insulin secretion. Brain is the
main organ regulating body weight, and the expression level of G5-R7 is much higher than in the pancreas or
any other peripheral tissues. These considerations lead to the hypothesis that G5-RGS7 regulates body
weight via its function in the CNS, where as in the insulin-secreting beta cells, G5-R7 can regulate hormone
and/or neurotransmitter secretion by neurons. In support of this hypothesis, recent studies in the lab
demonstrated that local knockout of Gnb5 in the hypothalamus using LoxP/Cre technology caused a dramatic
increase of body weight and adiposity in adult mice. The proposed research will develop this discovery.
Specific Aim 1 will analyze the effects of Gnb5 ablation in specific hypothalamic nuclei and types of neurons on
body weight and levels of various hormones. Overexpression of Gnb5 using viral-mediated gene transfer will
be performed to rescue obesity. Aim 2 will determine which hormones and signaling proteins (i.e., GPCRs) are
co-expressed with Gnb5 in hypothalamic neurons. Tissue and acutely cultured neurons will be examined for
secretion of specific hormones and signaling. Specific Aim 3 will study molecular events affected by G5-R7
via its knockout (CRISPR/Cas9), knockdown and overexpression in cell lines that endogenously express M3R
and G5-R7. Experiments will focus on signaling, structure-function analysis of G5-R7 and signal-stimulated
secretion utilizing pharmacological agents and biochemical and biophysical assays. Through unraveling a
novel mechanism that regulates neuronal functions, this project may have a strong impact on understanding
etiology of obesity and other neuroendocrine disorders.
抽象的
肥胖是糖尿病、癌症、心血管、神经系统和其他疾病的主要共病因素
疾病。最近与人类肥胖相关的一组基因是编码 R7 家族的基因
G 蛋白信号蛋白(RGS6、7、9 和 11)和 Gnb5(编码 G 蛋白 beta)的调节因子
亚基 G5。 G5 和 R7 蛋白形成强制性二聚体,因此 Gnb5 敲除会导致完全
整个 G5-R7 复合物的降解。该提案研究了 Gnb5 和 R7 基因缺陷如何影响
可能导致肥胖;最终目标是发现与以下疾病相关的有效治疗方法
神经内分泌途径受这些基因调节。
拟议的研究计划建立在早期发现的基础上,这些发现共同构成了强有力的前提
对于这项研究。消除一个 Gnb5 等位基因会导致小鼠肥胖和代谢综合征;这一发现是
后来被人类遗传学证实。该实验室随后的机制研究确定了
胰腺β细胞中的G5-R7复合物,其中G5-R7强烈促进胰岛素分泌。大脑是
是调节体重的主要器官,G5-R7的表达水平远高于胰腺或胰腺
任何其他外周组织。这些考虑导致了 G5-RGS7 调节身体的假设
通过其在 CNS 中的功能来调节体重,与分泌胰岛素的 β 细胞一样,G5-R7 可以调节激素
和/或神经元分泌的神经递质。为了支持这一假设,实验室最近的研究
证明使用 LoxP/Cre 技术局部敲除下丘脑中的 Gnb5 会导致显着的
成年小鼠体重和肥胖的增加。拟议的研究将进一步发展这一发现。
具体目标 1 将分析 Gnb5 消融对特定下丘脑核团和神经元类型的影响
体重和各种激素的水平。使用病毒介导的基因转移过度表达 Gnb5 将
来拯救肥胖症。目标 2 将确定哪些激素和信号蛋白(即 GPCR)是
与下丘脑神经元中的 Gnb5 共表达。将检查组织和急性培养的神经元
特定激素和信号的分泌。具体目标 3 将研究受 G5-R7 影响的分子事件
通过在内源性表达 M3R 的细胞系中进行敲除 (CRISPR/Cas9)、敲低和过表达
和G5-R7。实验将侧重于信号传导、G5-R7 的结构功能分析和信号刺激
利用药物制剂和生物化学和生物物理测定进行分泌。通过解开一个
调节神经元功能的新机制,该项目可能会对理解产生重大影响
肥胖和其他神经内分泌疾病的病因学。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Vladlen Z Slepak其他文献
Vladlen Z Slepak的其他文献
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{{ truncateString('Vladlen Z Slepak', 18)}}的其他基金
The role of regulator of G protein signaling Gbeta5-R7 in neuronal control of body weight
G蛋白信号调节剂Gbeta5-R7在神经元控制体重中的作用
- 批准号:
10539336 - 财政年份:2021
- 资助金额:
$ 19.19万 - 项目类别:
The role of regulator of G protein signaling Gbeta5-R7 in neuronal control of body weight
G蛋白信号调节剂Gbeta5-R7在神经元控制体重中的作用
- 批准号:
10096696 - 财政年份:2021
- 资助金额:
$ 19.19万 - 项目类别:
Gbeta5-R7 Complex in Signaling and Hormone Secretion
Gbeta5-R7 复合物在信号传导和激素分泌中的作用
- 批准号:
8864017 - 财政年份:2015
- 资助金额:
$ 19.19万 - 项目类别:
Gbeta5-R7 Complex in Signaling and Hormone Secretion
Gbeta5-R7 复合物在信号传导和激素分泌中的作用
- 批准号:
9137158 - 财政年份:2015
- 资助金额:
$ 19.19万 - 项目类别:
Light-dependent Transducin Movement in Retinal Rods.
视网膜杆中的光依赖性转导蛋白运动。
- 批准号:
7653955 - 财政年份:2009
- 资助金额:
$ 19.19万 - 项目类别:
Light-dependent Transducin Movement in Retinal Rods.
视网膜杆中的光依赖性转导蛋白运动。
- 批准号:
8458564 - 财政年份:2009
- 资助金额:
$ 19.19万 - 项目类别:
Light-dependent Transducin Movement in Retinal Rods.
视网膜杆中的光依赖性转导蛋白运动。
- 批准号:
8065978 - 财政年份:2009
- 资助金额:
$ 19.19万 - 项目类别:
Light-dependent Transducin Movement in Retinal Rods.
视网膜杆中的光依赖性转导蛋白运动。
- 批准号:
7805423 - 财政年份:2009
- 资助金额:
$ 19.19万 - 项目类别:
Light-dependent Transducin Movement in Retinal Rods.
视网膜杆中的光依赖性转导蛋白运动。
- 批准号:
8264353 - 财政年份:2009
- 资助金额:
$ 19.19万 - 项目类别:
REGULATION OF G PROTEIN GTPASE IN PHOTORECEPTORS
光感受器中 G 蛋白 GTP 酶的调节
- 批准号:
6384872 - 财政年份:2000
- 资助金额:
$ 19.19万 - 项目类别:
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