NUCLEUS TRACTUS SOLITARIUS MELANOCORTIN SIGNALING IN THE CONTROL OF FOOD INTAKE
孤束核黑皮质素信号传导控制食物摄入
基本信息
- 批准号:8219209
- 负责人:
- 金额:$ 5.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-02 至 2013-07-01
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAddressAgonistAnimal ModelAppetite DepressantsBasic ScienceBehaviorBiological AssayBody WeightBrain StemCell NucleusCholecystokininChronicClinical Drug DevelopmentCyclic AMP-Dependent Protein KinasesDataDevelopmentDrug Delivery SystemsEatingElementsEnergy MetabolismEventFeeding behaviorsFood EnergyGastrointestinal tract structureHealthHormonesHumanHyperphagiaImmunoblot AnalysisImmunoblottingIn VitroIntakeLigandsLinkMAPK3 geneMeasuresMediatingMediationMediator of activation proteinMelanocortin 4 ReceptorMetabolicMetabolic DiseasesMethodsMitogen-Activated Protein Kinase KinasesMitogen-Activated Protein KinasesMutationNeuronsNucleus solitariusNutrientObesityOverweightPathway interactionsPeptidesPeripheralPharmaceutical PreparationsPharmacological TreatmentPhysiologicalPhysiologyPopulationPrevalenceProductionPublic HealthRNA InterferenceReceptor ActivationReceptor GeneReceptor SignalingRegulationResearchRoleSHU 9119SatiationShapesSignal PathwaySignal TransductionSiteStomachSystemTechniquesTechnologycomputerized data processinggastrointestinalhindbrainin vivoinsightmelanocortin receptorneurochemistryobesity treatmentpublic health relevancerelating to nervous systemresearch studyresponsesmall hairpin RNAupstream kinase
项目摘要
DESCRIPTION (provided by applicant): Obesity prevalence is dramatically rising in Western cultures creating devastating and costly health problems. Mutations in the melanocortin 4-receptor (MC4-R) gene are the most common monogenetic cause of severe human obesity. The central melanocortin system is a promising target for clinical drug development for the treatment of obesity and related metabolic disorders, as MC4-R agonists potently suppress food intake and body weight in animal models. This proposal is relevant to clinical drug development and public health, as experiments have potential to yield insights into the mechanisms through which MC4-R signaling contributes to food intake suppression. The aims of this proposal are shaped by recent data showing that the nucleus tractus solitarius (NTS) of the caudal brainstem is a critical site of relevance to food intake control by MC4-R ligands, and that caudal brainstem MC4-R signaling is required for food intake suppression by exogenous cholecystokinin (CCK), the intestinally-derived satiation hormone. Experiments proposed in Specific Aim 1 will generate data that are necessary to more fully evaluate the hypothesis that caudal brainstem MC4-R signaling mediates the intake suppression triggered by various GI satiation signals. Caudal brainstem MC4-R antagonist treatment will be used to assess whether or not activation of these receptors is required for intake suppression following endogenous methods of GI satiation signaling, including intraintestinal nutrient delivery and gastric distention. Proposed research will also probe more deeply into the functional site of hindbrain MC4-R mediation of GI signals by examining the effects of parenchymal NTS MC4-R antagonist treatment on intake suppression by CCK. Adeno-associated virally-mediated knockdown of MC4-Rs in the NTS will be used as a complementary approach to antagonist treatment to assess the endogenous role of NTS MC4-Rs in mediating intake suppression by GI satiation signals. Importantly, MC4-R knockdown technology will also be used to assess the role of endogenous NTS MC4-R signaling in energy regulation more generally. Experiments proposed in Specific Aim 2 will expand consideration to the intracellular signaling pathways in the NTS contributing to intake suppression following MC4-R agonists, GI satiation signaling, and their putative combination. Proposed research will build upon our preliminary findings and other recent data by targeting the p44/42 mitogen-activated protein kinase (MAPK) signaling pathway and potential upstream kinases (protein kinase A [PKA] and phosphatidylinositol 3-kinase [PI3K]) as NTS intracellular mediators of intake suppression by MC4-R ligands and GI signals. Experiments will combine in vivo approaches using pharmacological inhibition of p44/42 MAPK, PKA, and PI3K, with in vitro approaches using activity assays and immunoblots, to assess the physiological role of these intracellular signaling pathways in the suppression of intake that follows MC4-R ligands, GI satiation signals, and potentially their combination. Research laid out in this proposal has the potential to deepen the basic science related to neurochemical mediators of food intake suppression.
PUBLIC HEALTH RELEVANCE: The prevalence of obese and overweight humans in Western cultures has increased dramatically, leading to devastating and costly health problems. Effective drug treatments for obesity treatment are likely to come from basic science investigating the neuronal controls of food intake behavior. Research proposed here is relevant to clinical drug development for obesity by exploring neurohormonal mediators of food intake suppression following gastrointestinal contact with ingested nutrients and the processing of these signals by the human obesity-linked melanocortin receptors in the caudal brainstem.
描述(申请人提供):肥胖率在西方文化中急剧上升,造成了毁灭性的和代价高昂的健康问题。黑素皮质素4受体(MC4-R)基因突变是导致人类严重肥胖的最常见的单基因原因。中枢黑素皮质素系统是治疗肥胖和相关代谢紊乱的临床药物开发的一个有希望的靶点,因为MC4-R激动剂在动物模型中有效地抑制食物摄入量和体重。这一建议与临床药物开发和公共健康有关,因为实验有可能深入了解MC4-R信号有助于抑制食物摄入的机制。最近的数据表明,尾侧脑干孤束核(NTS)是与MC4-R配体控制食物摄取相关的关键部位,而尾部脑干MC4-R信号是外源性CCK(肠源性饱腹素)抑制食物摄取所必需的。在特定目标1中提出的实验将产生必要的数据,以更全面地评估尾侧脑干MC4-R信号介导由各种GI饱和信号触发的摄取抑制这一假说。尾侧脑干MC4-R拮抗剂治疗将用于评估是否需要激活这些受体来抑制内源性GI饱足信号的摄入,包括肠道内营养输送和胃胀。拟议的研究还将通过检测NTS MC4-R拮抗剂对CCK抑制摄取的影响,更深入地探讨后脑MC4-R介导GI信号的功能部位。腺相关病毒介导的NTS中MC4-Rs的下调将作为拮抗剂治疗的补充方法,以评估NTS MC4-Rs在介导胃肠道饱和信号抑制摄取中的内源性作用。重要的是,MC4-R基因敲除技术也将被用来评估内源性NTS MC4-R信号在能量调节中的作用。在特定目标2中提出的实验将扩展到在MC4-R激动剂、GI饱和信号和它们的假定组合之后,NTS中有助于抑制摄取的细胞内信号通路。建议的研究将以我们的初步发现和其他最新数据为基础,将p44/42丝裂原活化蛋白激酶(MAPK)信号通路和潜在的上游激酶(蛋白激酶A[PKA]和磷脂酰肌醇3-激酶[PI3K])作为NTS细胞内介质,以抑制MC4-R配体和GI信号的摄取。实验将结合体内使用药物抑制p44/42 MAPK、PKA和PI3K的方法,以及使用活性分析和免疫印迹的体外方法,来评估这些细胞内信号通路在抑制MC4-R配体、GI饱和信号以及它们的潜在组合后的摄取的生理作用。这项提案中提出的研究有可能深化与抑制食物摄入的神经化学介质相关的基础科学。
与公共卫生相关:在西方文化中,肥胖和超重的人的流行率急剧增加,导致了毁灭性的和代价高昂的健康问题。肥胖症的有效药物治疗很可能来自于研究神经元控制食物摄入行为的基础科学。这里提出的研究与肥胖的临床药物开发相关,通过探索胃肠道与摄入的营养物质接触后抑制食物摄入的神经激素介质,以及人类尾侧脑干中与肥胖相关的黑素皮质素受体对这些信号的处理。
项目成果
期刊论文数量(0)
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Scott Edward Kanoski其他文献
Scott Edward Kanoski的其他文献
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{{ truncateString('Scott Edward Kanoski', 18)}}的其他基金
Control of feeding behavior by melanin-concentrating hormone
黑色素浓缩激素控制进食行为
- 批准号:
10152596 - 财政年份:2018
- 资助金额:
$ 5.13万 - 项目类别:
Control of feeding behavior by melanin-concentrating hormone
黑色素浓缩激素控制进食行为
- 批准号:
9923654 - 财政年份:2018
- 资助金额:
$ 5.13万 - 项目类别:
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