Molecular Mechanisms of AgRP Signaling
AgRP 信号传导的分子机制
基本信息
- 批准号:9309934
- 负责人:
- 金额:$ 45.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-05-01 至 2021-04-30
- 项目状态:已结题
- 来源:
- 关键词:ART proteinAffinityAlpha CellAmino Acid SequenceAnimalsAnorexiaAppetite StimulantsBehaviorBindingBiophysicsBloodBody WeightBolus InfusionBrainCell surfaceChargeChemicalsCholesterolCollaborationsComplexConeCoronary ArteriosclerosisCouplingCyclic AMPCyclizationCystineDiabetes MellitusDiseaseElectrophysiology (science)Energy IntakeEnergy MetabolismEnhancersFamilyFeeding behaviorsG-Protein-Coupled ReceptorsG-substrateGTP-Binding Protein alpha Subunits, GsGlycosaminoglycansGoalsHomeostasisHormonalHumanHypertensionHypothalamic structureImageInjection of therapeutic agentKnockout MiceLeadLeptinLigand BindingLigandsLinkMalignant NeoplasmsMediatingMelanocortin 3 ReceptorMelanocortin 4 ReceptorMembraneMetabolicMetabolic ControlMetabolic DiseasesMetabolismMolecularMolecular ConformationMutationNeuronsObesityPeptidesPeripheralPharmacologyPhysiologicalPlayPotassium ChannelProductionProtein ConformationProtein EngineeringProteinsProteoglycanProteolysisPublic HealthPublishingRattusRegulationResearchResistanceRoleScaffolding ProteinSecond Messenger SystemsSignal TransductionSignaling ProteinSocietiesStructureSurfaceSystemTechniquesTestingThermodynamicsThinnessTimeTissue imagingTissuesVariantVertebral columnWasting SyndromeWeight GainWorkalpha-Melanocyte stimulating hormoneanalogappetite lossbasebrain tissuecancer cachexiacrosslinkdesignenergy balanceexomeexome sequencingexperimental studyfeedingimprovedin vivoinhibitor/antagonistinward rectifier potassium channelmelanocortin receptormembermutantneural circuitnovelnovel therapeutic interventionnutrient deprivationprogramsprotein structurereceptorresponsestructural biologysyndecansyndecan 3waste treatmentwasting
项目摘要
Project Summary
In the brain, key focal points for control of metabolic function and feeding behavior are
melanocortin receptors MC3R and MC4R. These receptors respond to two ligands,
alpha-melanocyte stimulating hormone (a-MSH) and the agouti-related protein (AgRP),
which act in opposite ways to promote negative and positive energy balance,
respectively. Recent research demonstrates the profound importance of AgRP releasing
neurons in metabolism and body weight homeostasis. The goal of this program is to
understand the molecular basis of AgRP action, thus enabling new strategies for treating
diverse conditions linked to obesity and metabolic diseases. New findings from our lab
are significantly reshaping our understanding of a-MSH and AgRP action. The current
paradigm posits that these molecules act to stimulate or suppress production of the
cAMP second messenger. However, using protein design, we demonstrated that AgRP
mutations in segments outside of the MCR binding core exert a profound influence on
long term feeding, while leaving receptor affinity and cAMP suppression completely
unchanged relative to wild-type. Moreover, new collaborative results find that AgRP
promotes the opening of inward rectifying potassium channels through a cAMP
independent mechanism, an effect that is directly dependent on these peripheral AgRP
segments. Aim 1 of this application will expand these studies by identifying how AgRP
sequence and conformation drive potassium channel currents. This will be tested
through protein design, NMR structure determination, as well as with a new human
AgRP obesity-linked mutant identified by whole exome analysis. Aim 2 will examine how
syndecan-3, a negatively charged, membrane bound proteoglycan, facilitates AgRP
signaling. This will be accomplished with biophysical experiments and through
comparison studies where designed proteins are administered to wild-type and
syndecan-3 knockout mice, followed by feeding trials and brain tissue imaging. Aim 3
will expand on AgRP design efforts to produce stable proteins to test the role of
proteolytic resistance in promoting long-term AgRP action, and as leads for treating
cancer cachexia, a wasting condition characterized by extreme loss of appetite and lean
tissue degradation.
项目摘要
在大脑中,控制新陈代谢功能和摄食行为的关键焦点是
黑素皮质素受体MC3R和MC4R。这些受体与两种配体反应,
α-黑素细胞刺激素(a-MSH)和刺鼠相关蛋白(AgRP),
它们以相反的方式促进正负能量平衡,
分别进行了分析。最近的研究证明了AgRP释放的深远重要性
神经元在代谢和体重动态平衡中的作用。这项计划的目标是
了解AgRP作用的分子基础,从而实现新的治疗策略
与肥胖和代谢性疾病有关的各种情况。我们实验室的新发现
极大地改变了我们对α-MSH和AgRP作用的理解。海流
范式假设,这些分子的作用是刺激或抑制
夏令营第二信使。然而,使用蛋白质设计,我们证明了AgRP
MCR结合核心外片段的突变对
长期喂养,同时完全离开受体亲和力和cAMP抑制
与野生型相比没有变化。此外,新的合作结果发现,AgRP
通过cAMP促进内向整流钾通道的开放
独立的机制,这种作用直接依赖于这些外周AgRP
细分市场。本应用程序的目标1将通过确定AgRP如何
序列和构象驱动钾通道电流。这将会被测试
通过蛋白质设计、核磁共振结构测定,以及与新人类
全外显子组分析鉴定AgRP肥胖连锁突变。Aim 2将研究如何
Syndecan-3,一种带负电荷的膜结合蛋白多糖,促进AgRP
发信号。这将通过生物物理实验和通过
将设计的蛋白质用于野生型和野生型的比较研究
Syndecan-3基因敲除小鼠,随后进行喂养试验和脑组织成像。目标3
将在AgRP设计上展开努力,以生产稳定的蛋白质来测试其作用
蛋白分解抵抗促进AgRP的长期作用,并作为治疗的先导
癌症恶病质,一种以极度食欲不振和消瘦为特征的消瘦状态
组织退化。
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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GLENN L MILLHAUSER其他文献
GLENN L MILLHAUSER的其他文献
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{{ truncateString('GLENN L MILLHAUSER', 18)}}的其他基金
Discovering How Cu(II)/Zn(II) Uptake by the Prion Protein Controls Structure, Function and Neurotoxicity
发现朊病毒蛋白摄取 Cu(II)/Zn(II) 如何控制结构、功能和神经毒性
- 批准号:
9914103 - 财政年份:2019
- 资助金额:
$ 45.11万 - 项目类别:
Discovering How Cu(II)/Zn(II) Uptake by the Prion Protein Controls Structure, Function and Neurotoxicity
发现朊病毒蛋白摄取 Cu(II)/Zn(II) 如何控制结构、功能和神经毒性
- 批准号:
10396527 - 财政年份:2019
- 资助金额:
$ 45.11万 - 项目类别:
Discovering How Cu(II)/Zn(II) Uptake by the Prion Protein Controls Structure, Function and Neurotoxicity
发现朊病毒蛋白摄取 Cu(II)/Zn(II) 如何控制结构、功能和神经毒性
- 批准号:
10612778 - 财政年份:2019
- 资助金额:
$ 45.11万 - 项目类别:
Molecular control of melanocortin receptor signaling
黑皮质素受体信号传导的分子控制
- 批准号:
8000165 - 财政年份:2010
- 资助金额:
$ 45.11万 - 项目类别:
Catechol-induced Inhibition of Alpha-synuclein Fibrils
儿茶酚诱导的α-突触核蛋白原纤维的抑制
- 批准号:
7367908 - 财政年份:2005
- 资助金额:
$ 45.11万 - 项目类别:
Molecular control of melanocortin receptor signaling
黑皮质素受体信号传导的分子控制
- 批准号:
7676549 - 财政年份:2003
- 资助金额:
$ 45.11万 - 项目类别:
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