Targeting the GDF15-GFRAL system to treat nausea and emesis
靶向 GDF15-GFRAL 系统治疗恶心和呕吐
基本信息
- 批准号:10630836
- 负责人:
- 金额:$ 67.01万
- 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:2021-08-09 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAblationAffinityAnorexiaAntibodiesAntiemeticsAppetite DepressantsAreaAttentionAttenuatedBase SequenceBehaviorBehavioralBehavioral AssayBindingBiological AssayBody WeightBody Weight decreasedBrain StemCachexiaCell NucleusCellsCellular Metabolic ProcessChronicChronic DiseaseCirculationCisplatinClinicalComplexDataDevelopmentDiabetes MellitusDiseaseDistressDrug KineticsEmeticsEndotheliumEquilibriumFamilyFeeding behaviorsFluorescent in Situ HybridizationGDF15 geneGenerationsGoalsHealthHumanHungerIn VitroKnockout MiceLeadLegal patentLesionLinkLiteratureMalaiseMalignant NeoplasmsMeasuresMediatingMediatorMedicineMetabolic DiseasesMicrogliaModelingMolecularMolecular ConformationMusNauseaNausea and VomitingNeurobiologyNeuronsObesityOutputPainPaperPathologicPenetrationPeptidesPeripheralPharmacodynamicsPharmacotherapyPhenotypePlasmaPlayPregnancyProcessProductionPublishingRattusRegulationReportingResearch PersonnelRodentRoleScienceSerumShrewsSick RoleSignal TransductionSiteStimulusStressStructureStructure of area postremaSyndromeSystemTechnologyTestingTissuesVomitingWeight Gainanalogantagonistbehavioral pharmacologycancer anorexiacancer therapychemotherapycytokineenergy balanceexperiencefeedinggenomic platformglial cell-line derived neurotrophic factorimprovedin vivoin vivo evaluationinhibitorneuralnovelobesity treatmentrational designreceptorresponsetraffickingtranscriptometranscriptomics
项目摘要
Summary
The growth differentiation factor 15 (GDF15), formerly known as macrophage inhibitory cytokine-1 (MIC-1),
is a cytokine that shows expression and serum rise in response to many conditions and diseases, including
pregnancy, obesity, diabetes, and cancer. GDF15 signaling has gained significant attention in recent years with
multiple papers in 2017 identifying the GDNF family receptor α-like ( GFRAL ) receptor as binding GDF15
selectivelyand with high affinity. However, the reported restrictive expression of the GFRAL receptor to the
area postrema (AP) and nucleus tractus solitarius (NTS) of the brainstem, areas highly critical to both energy
balance and emesis/nausea/malaise suggests that GDF15-GFRAL signaling could be an important factor not only
in long-term body weight regulation, but also in short-term processing of emesis and illness. Behavior. Thus,
understanding what role GDF15-GFRAL signaling plays in illness behavior and anorexia is paramount to
determining the mechanism of GDF15 action. Compelling evidence links GDF15 signaling with chemotherapy-
induced nausea and anorexia, which remain important clinical problems despite relatively well-controlled
chemotherapy-induced emesis, by showing that: 1) GDF15 signaling causes nausea and emesis; 2) an AP/NTS
site of action is responsible for mediating the feeding effects of GDF15 signaling through binding of the GFRAL-
RET receptor complex, and 3) obesity, cancer, and chemotherapy increase circulating GDF15 in rodents and
humans. We hypothesize that a functional dynamic change in the expression of central GDF15 levels in the NTS
and AP will occur following energy balance dysregulation and/or administration of emetic stimuli, and that we
can mitigate/treat such through the unique molecular and behavioral assays and patented peptide-based
technology employed here (i.e. our
peptide-based
inhibitor
bind
nausea
novel GFRAL-RET antagonist “GRASP”). The GRASP antagonist is a small,
sequence with our in vivo and conformational binding models supporting it to be an allosteric
to the GFRAL-RET complex. We have also shown that GRASP can penetrate into the brainstem and
to GFRAL-expressing neurons in the AP/NTS, and consequently attenuate GDF15- and cisplatin-induced
behaviors in rats.To further explore the GDF15-GFRAL system, we propose complimentary studies by a
multi-PI team of established investigators with extensive collaborative experience to investigate the following
aims: Aim I will characterize brainstem circuitry and unbiased single cell transcriptomics for endogenous GDF15
production and GFRAL/RET-expressing neuronal phenotypes. Aim II will characterize GDF15-induced emesis,
nausea behavior, and anorexia as well as characterize the GRASP lead compound against these behaviors with a
multi-species approach. Aim III will characterize the critical mechanistic and stability parameters of GRASP
through rational design of analogs based on functional, computational and structural data to build upon our
successful technology to-date that seeks to block the GFRAL receptor to treat sickness measures that include
unwanted anorexia, nausea and emesis.
总结
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Unraveling Psychiatric Disorders through Neural Single-Cell Transcriptomics Approaches.
- DOI:10.3390/genes14030771
- 发表时间:2023-03-22
- 期刊:
- 影响因子:3.5
- 作者:
- 通讯作者:
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{{ truncateString('Bart C DE JONGHE', 18)}}的其他基金
Targeting the GDF15-GFRAL system to treat nausea and emesis
靶向 GDF15-GFRAL 系统治疗恶心和呕吐
- 批准号:
10463832 - 财政年份:2021
- 资助金额:
$ 67.01万 - 项目类别:
Second generation GLP-1 agonists without nausea/emesis side effects
第二代 GLP-1 激动剂,无恶心/呕吐副作用
- 批准号:
10183954 - 财政年份:2021
- 资助金额:
$ 67.01万 - 项目类别:
Targeting the GDF15-GFRAL system to treat nausea and emesis
靶向 GDF15-GFRAL 系统治疗恶心和呕吐
- 批准号:
10312414 - 财政年份:2021
- 资助金额:
$ 67.01万 - 项目类别:
Second generation GLP-1 agonists without nausea/emesis side effects
第二代 GLP-1 激动剂,无恶心/呕吐副作用
- 批准号:
10577892 - 财政年份:2021
- 资助金额:
$ 67.01万 - 项目类别:
Second generation GLP-1 agonists without nausea/emesis side effects
第二代 GLP-1 激动剂,无恶心/呕吐副作用
- 批准号:
10357951 - 财政年份:2021
- 资助金额:
$ 67.01万 - 项目类别:
Neural Mechanisms of Nausea, Vomiting, and Energy Dysregulation
恶心、呕吐和能量失调的神经机制
- 批准号:
10752271 - 财政年份:2017
- 资助金额:
$ 67.01万 - 项目类别:
Neural mechanisms of nausea, vomiting, and energy balance dysregulation in animal models
动物模型中恶心、呕吐和能量平衡失调的神经机制
- 批准号:
9895765 - 财政年份:2017
- 资助金额:
$ 67.01万 - 项目类别:
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