GPR35 on Vagal Afferent Neurons as a Peripheral Drug Target for Treating Diet-Induced Obesity
迷走神经传入神经元上的 GPR35 作为治疗饮食引起的肥胖的外周药物靶点
基本信息
- 批准号:10470747
- 负责人:
- 金额:$ 2.38万
- 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:2021-09-01 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:AffectAfferent NeuronsAgonistAppetitive BehaviorBehavior TherapyBehavior monitoringBifidobacteriumBody WeightBody Weight decreasedBrainCalciumCaloriesCardiovascular DiseasesCell NucleusCholecystokininCholecystokinin ReceptorChronic DiseaseConsumptionDataDevelopmentDietDrug TargetingEatingEffectivenessEnergy IntakeFOS geneFeeding behaviorsFutureGPR35 geneGTP-Binding Protein alpha Subunits, GsGastrointestinal tract structureGoalsHigh Fat DietHormonesHumanHuman MilkHyperphagiaImageImpairmentIn SituIn VitroIntestinesKynurenic AcidKynurenineLifeLigandsMeasuresMediatingMentorshipMetabolic DiseasesMorbid ObesityMorbidity - disease rateMusNeuronsObesityOligosaccharidesOperative Surgical ProceduresPathway interactionsPeripheralPersonsPhosphorylationPlasmaPrevalenceProbioticsProductionPublishingRNA InterferenceReducing dietRisk FactorsRodent ModelRoleSatiationSignal TransductionSiteSourceTechniquesTestingTrainingUnited StatesWeight GainWestern BlottingWorkantagonistbariatric surgerycostdesensitizationdiet-induced obesityeffective therapyexperimental studygut microbiotahost microbiotahuman modelin vivointravital imagingknock-downmicrobialmicrobiota-gut-brain axismouse modelnovel therapeutic interventionobesity managementobesity treatmentprebioticspreservationreceptorreduced food intakeresponsetherapeutic targetzaprinast
项目摘要
PROJECT SUMMARY
Obesity is a major risk factor for chronic diseases, such as cardiovascular and metabolic diseases, and its
global prevalence parallels the overconsumption of calorie-dense diets. Gastric bypass surgery is currently the
only effective treatment for maintaining weight loss. However, surgery is expensive, invasive, and reserved for
people with severe obesity. The effectiveness of gastric bypass surgery is partly attributed to a shift in the
composition of the gut microbiota and microbial metabolites, and to the increased production of peripheral
satiety hormones. Vagal afferent neurons (VANs) are located in the gut wall, express receptors for peripheral
hormones and microbial metabolites, and transmit satiety signals from the gastrointestinal tract to the brain to
inhibit food intake. The G-protein coupled receptor 35 (GPR35) is activated by microbial metabolites and is
highly expressed on VANs. Recent evidence demonstrates GPR35 on VANs is co-localized with CCKAR, the
receptor for mediating the satiety-inducing effects of the enteroendocrine hormone, cholecystokinin (CCK).
Desensitization of VANs to intestinal satiety signals, including CCK, precedes high-fat diet-induced weight gain
and hyperphagia in mouse models of human obesity and leads to increased food intake. High-fat diet has been
shown to reduce plasma levels of kynurenic acid, a microbial metabolite that is an endogenous GPR35 ligand.
However, the role of GPR35 in peripheral satiety signaling is unknown. Preliminary data show that activation of
GPR35 using the GPR35 agonist, zaprinast, decreases food intake in mice and in vitro experiments
demonstrate that GPR35 inhibition decreases the sensitivity of VANs to CCK. Therefore, we hypothesize that
high-fat diet decreases the production of microbially-derived GPR35 ligands, leading to reduced VAN
sensitivity to CCK, suppression of intestinal satiety signaling thereby increasing energy intake. The hypothesis
will be tested in two aims. Aim 1 will determine the interaction of CCKAR and GPR35 in activation of VANs and
second order neurons in the brain, and in inhibiting food intake. Aim 2 will determine whether increasing
availability of GPR35 ligands, either by administration of prebiotics or probiotics, can restore HF-diet induced
impairment of VANs and control food intake. The hypothesis will be tested using a combination of in vitro,
intravital, and in vivo techniques including calcium imaging, RNA interference knockdown of GPR35 in VANs,
and automated feeding behavior monitoring. Successful completion of these studies will demonstrate the role
of GPR35 in peripheral satiety signaling and reveal a potential therapeutic target for treating obesity. The
training plan will be facilitated by the mentorship of my sponsor and the exceptional facilities at UC Davis. This
proposal describes an integrative and comprehensive training plan to support scientific and professional
development and propel me toward my long-term goal of becoming an integrative physiologist.
项目总结
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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Danielle Lorena Zumpano其他文献
Danielle Lorena Zumpano的其他文献
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{{ truncateString('Danielle Lorena Zumpano', 18)}}的其他基金
GPR35 on Vagal Afferent Neurons as a Peripheral Drug Target for Treating Diet-Induced Obesity
迷走神经传入神经元上的 GPR35 作为治疗饮食引起的肥胖的外周药物靶点
- 批准号:
10315571 - 财政年份:2021
- 资助金额:
$ 2.38万 - 项目类别:
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