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:10312414
- 负责人:
- 金额:$ 68.38万
- 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:2021-08-09 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAblationAffinityAnorexiaAntibodiesAntiemeticsAppetite DepressantsAreaAttentionAttenuatedBase SequenceBehaviorBehavioralBehavioral AssayBindingBiological AssayBlood CirculationBody WeightBody Weight decreasedBrain StemCachexiaCell NucleusCellsCellular Metabolic ProcessChemotherapy-Oncologic ProcedureChronicChronic DiseaseCisplatinClinicalComplexDataDevelopmentDiabetes MellitusDiseaseDistressDrug KineticsEmeticsEndotheliumEquilibriumFamilyFeeding behaviorsFluorescent in Situ HybridizationGDF15 geneGenerationsGoalsHealthHumanHungerIn VitroKnockout MiceLeadLegal patentLesionLinkLiteratureMalaiseMalignant NeoplasmsMeasuresMediatingMediator of activation proteinMedicineMetabolic DiseasesMicrogliaModelingMolecularMolecular ConformationMusNauseaNausea and VomitingNeurobiologyNeuronsObesityOutputPainPaperPathologicPeptidesPeripheralPharmacodynamicsPharmacotherapyPhenotypePlasmaPlayPregnancyProcessProductionPublishingRattusRegulationReportingResearch PersonnelRodentRoleScienceSerumShrewsSick RoleSignal TransductionSiteStimulusStressStructureStructure of area postremaSyndromeSystemTechnologyTestingTissuesVomitingWeight Gainanalogbasebehavioral pharmacologycancer anorexiachemotherapycytokinedesignenergy balanceexperiencefeedinggenomic platformglial cell-line derived neurotrophic factorimprovedin vivoin vivo evaluationinhibitor/antagonistnovelobesity treatmentreceptorrelating to nervous systemresponsetraffickingtranscriptometranscriptomics
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
生长分化因子15(GDF 15),以前称为巨噬细胞抑制性细胞因子-1(MIC-1),
是一种细胞因子,其在响应许多病症和疾病时显示表达和血清升高,包括
怀孕肥胖糖尿病和癌症近年来,GDF 15信号传导获得了显著的关注,
2017年的多篇论文将GDNF家族受体α样(GFRAL)受体鉴定为结合GDF 15
选择性和高亲和力。然而,所报道的GFRAL受体限制性表达于
脑干的最后区(AP)和孤束核(NTS),这些区域对这两种能量都非常关键
平衡和呕吐/恶心/不适表明GDF 15-GFRAL信号传导不仅是一个重要因素,
在长期的体重调节,而且在短期的呕吐和疾病的处理。行为因此,在本发明中,
了解GDF 15-GFRAL信号在疾病行为和厌食症中的作用至关重要,
确定GDF 15作用的机制。令人信服的证据将GDF 15信号传导与化疗联系起来-
引起的恶心和厌食,尽管控制相对良好,但仍然是重要的临床问题
通过显示:1)GDF 15信号传导引起恶心和呕吐; 2)AP/NTS
作用位点负责介导GDF 15信号传导的摄食作用,通过GFRAL-1的结合。
RET受体复合物,和3)肥胖,癌症和化疗增加啮齿类动物中的循环GDF 15,
人类我们假设NTS中枢GDF 15表达水平的功能性动态变化可能与NTS中GDF 15表达水平的变化有关。
和AP将在能量平衡失调和/或给予催吐刺激后发生,
可以通过独特的分子和行为分析以及基于专利肽的
技术(即我们的
基于肽
抑制剂
结合
恶心
新GFRAL-RET拮抗剂“GRASP”)。GRASP拮抗剂是一种小,
序列与我们的体内和构象结合模型支持它是一个变构
GFRAL-RET复合体我们还表明,GRASP可以渗透到脑干,
AP/NTS中GFRAL表达神经元,从而减弱GDF 15和顺铂诱导的GFRAL表达。
为了进一步探索GDF 15-GFRAL系统,我们提出了一个免费的研究,
由具有丰富合作经验的资深研究者组成的多PI团队,以研究以下内容
目的:目的我将表征脑干回路和无偏倚的单细胞转录组学内源性GDF 15
产生和表达GFRAL/RET的神经元表型。Aim II将描述GDF 15诱导的呕吐,
恶心行为和厌食症,并以
多物种方法。目标三将描述大型类人猿生存项目的关键机制和稳定性参数
通过基于功能、计算和结构数据合理设计类似物,以我们的
迄今为止,成功的技术试图阻断GFRAL受体来治疗疾病,包括
不必要的厌食恶心和呕吐
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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{{ 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:
$ 68.38万 - 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:
$ 68.38万 - 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:
10630836 - 财政年份:2021
- 资助金额:
$ 68.38万 - 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:
$ 68.38万 - 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:
$ 68.38万 - 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:
$ 68.38万 - 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:
$ 68.38万 - 项目类别:
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