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
基本信息
- 批准号:10539336
- 负责人:
- 金额:$ 49.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-28 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAcuteAdultAffectAgonistAllelesAnimalsAntibodiesBeta CellBody WeightBrainCRISPR/Cas technologyCardiovascular DiseasesCardiovascular systemCell LineCell NucleusCell physiologyCentral Nervous SystemComplexControlled EnvironmentDataDiabetes MellitusDiagnosisDiseaseEnergy IntakeEquilibriumEtiologyEventFamilyG-Protein-Coupled ReceptorsGNB5 geneGTP-Binding Protein RegulatorsGTP-Binding Protein beta SubunitsGTP-Binding ProteinsGene TransferGenesGeneticGoalsGrowthHeterozygoteHomeostasisHormone secretionHormonesHumanHuman GeneticsHypothalamic HormonesHypothalamic structureIn SituIn VitroInjectionsInulinInvestigationKidney DiseasesKnock-outLinkMalignant NeoplasmsMapsMeasuresMessenger RNAMetabolicMetabolic DiseasesMetabolic syndromeMetabolismMolecularMusMuscarinic Acetylcholine Receptor M3MutationNeuroendocrinologyNeurologicNeuronsNeurosecretory SystemsNeurotransmittersNon-Insulin-Dependent Diabetes MellitusObesityOrganPancreasPathologicPathway interactionsPatternPeripheralPhenotypePhosphorylationPhysiologicalPlayPopulationProteinsRGS ProteinsRegulationResearchRisk FactorsRoleSecond Messenger SystemsSeriesSignal TransductionSignaling ProteinSliceStimulusStrokeStructureStructure of beta Cell of isletSystemTestingTissuesViral GenesViral VectorWeight Gainbiological systemscholinergiccomorbiditydimereffective therapyenergy balanceexperimental studyextracellularin vivoinsightinsulin secretionkinase inhibitorknock-downknockout genemutantnervous system disordernovelnovel therapeutic interventionoverexpressionpeptide hormonepharmacologicprotein complexreal-time imagesresponse
项目摘要
Obesity is a major co-morbidity factor in diabetes, cancer, cardiovascular, neurological and other
diseases. Recently, a new group of human genes was linked to obesity, the genes encoding the R7 family
of regulator of G protein signaling proteins (RGS6, 7, 9 and 11) and Gnb5, which encodes the atypical G
protein beta subunit Gb5. This proposal studies how a deficiency in the Gnb5 and R7 genes can lead to
obesity and other abnormalities in control of body weight. 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. Gb5 and R7 proteins form obligatory dimers, so that the Gnb5 knockout causes
complete degradation of the entire Gb5-R7 complex. 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 Gb5-R7 complex in pancreatic beta cells where Gb5-
R7 strongly promoted secretion of insulin. Brain is the main organ regulating body weight, and the
expression level of Gb5-R7 is much higher in the CNS than in the pancreas or any other peripheral tissues.
These considerations lead us to the hypothesis that Gb5-RGS7 regulates body weight via its function in
the neurons, where, similarly to the insulin-secreting beta cells, it controls secretion of neurotransmitters
and hormones. In support of this hypothesis, recent studies in the lab demonstrated that local knockout of
Gnb5 in the adult mouse hypothalamus dramatically increased body and adiposity. The proposed
experiments will develop this discovery through a series of experiments performed at the organismal,
tissue and cellular levels. Specific Aim 1 will use the Cre-loxP approach to inactivate Gnb5 in specific
hypothalamic nuclei and types of neurons and examine the effect of the knockout on body weight and
metabolism. Overexpression of Gnb5 using viral gene transfer will be performed to rescue the changes
caused by the knockout. Aim 2 will study co-expression of Gnb5 with GPCRs and gene encoding
hypothalamic hormones and tissue slices will be examined ex vivo for signal-stimulated secretion of
specific hormones. Specific Aim 3 will study Gb5-R7 its knockout (CRISPR/Cas9), knockdown and
overexpression in cell lines that endogenously express Gb5-R7. Experiments will utilize pharmacological
agents and structure-function analysis to interrogate molecular events in signaling and secretory pathways.
The proposed investigation of the Gb5-R7 complex will elucidate the novel mechanism regulating secretion
of hypothalamic hormones and significantly advance our understanding of G protein signaling, etiology of
obesity and other metabolic and neuroendocrine disorders.
肥胖是糖尿病、癌症、心血管疾病、神经疾病和其他疾病的主要共同发病因素
疾病。最近,一组新的人类基因被认为与肥胖有关,即编码R7家族的基因
G蛋白信号蛋白的调节蛋白(RGS6、7、9和11)和编码非典型G蛋白的Gnb5
蛋白β亚基GB5。这项建议研究了Gnb5和R7基因的缺陷如何导致
肥胖和其他控制体重的异常。最终的目标是发现有效的
与这些基因调控的神经内分泌通路相关的疾病的治疗。
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一个强大的
这是本研究的前提。GB5和R7蛋白形成必需的二聚体,因此Gnb5基因敲除导致
整个GB5-R7复合体完全降解。一个Gnb5等位基因的缺失会导致肥胖和
老鼠的代谢综合征;这一发现后来被人类遗传学证实。后继机械论
本实验室的研究证实了GB5-R7复合体在胰岛β细胞中的一个新作用,其中GB5-R7-
R7强烈促进胰岛素的分泌。大脑是调节体重的主要器官,而
GB5-R7在中枢神经系统中的表达水平明显高于胰腺或其他任何外周组织。
这些考虑导致了我们的假设,GB5-RGS7通过其在体内的功能调节体重
神经元,类似于分泌胰岛素的β细胞,它控制神经递质的分泌
和荷尔蒙。为了支持这一假说,实验室最近的研究表明,局部敲除
成年小鼠下丘脑中的GNB5显著增加了身体和肥胖。建议数
实验将通过在有机体上进行的一系列实验来发展这一发现,
组织和细胞水平。特定目标1将使用Cre-loxP方法来灭活特定的
下丘脑核团和神经元类型,并检测基因敲除对体重和
新陈代谢。将通过病毒基因转移过表达Gnb5来挽救这些变化
由淘汰赛引起的。目标2将研究Gnb5与GPCRs和编码基因的共表达
下丘脑激素和组织切片将在体外检查信号刺激的分泌
特定荷尔蒙。特定目标3将研究GB5-R7 ITS敲除(CRISPR/Cas9)、击倒和
在内源性表达GB5-R7的细胞系中过表达。实验将利用药理学
药物和结构-功能分析,以询问信号和分泌途径中的分子事件。
拟议的对GB5-R7复合体的研究将阐明调节分泌的新机制
并大大促进了我们对G蛋白信号转导的理解,
肥胖和其他代谢和神经内分泌疾病。
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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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:
10096696 - 财政年份:2021
- 资助金额:
$ 49.28万 - 项目类别:
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
- 批准号:
10001791 - 财政年份:2019
- 资助金额:
$ 49.28万 - 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:
$ 49.28万 - 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:
$ 49.28万 - 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:
$ 49.28万 - 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:
$ 49.28万 - 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:
$ 49.28万 - 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:
$ 49.28万 - 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:
$ 49.28万 - 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:
$ 49.28万 - 项目类别:
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