Identifying endogenous peptide ligands for orphan G protein-coupled receptors to explore their roles in CNS disorders
鉴定孤儿 G 蛋白偶联受体的内源性肽配体,探索其在中枢神经系统疾病中的作用
基本信息
- 批准号:10701897
- 负责人:
- 金额:$ 21.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-15 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Adenylate CyclaseAgonistAlzheimer&aposs DiseaseArrestinsBehaviorBindingBinding SitesBiologicalBiological AssayBrainCNR1 geneCalciumCellsCentral Nervous SystemCentral Nervous System DiseasesCholera ToxinCollaborationsConserved SequenceDetectionDevelopmentDiseaseEnzymesFDA approvedG-Protein-Coupled ReceptorsGasesGenomeGlutaminaseGrantHumanIndividualKnowledgeKnowledge Management CenterLaboratoriesLibrariesLigand BindingLigandsMeasuresMediatingMental DepressionMessenger RNAMood DisordersMusNamesNeuropeptide ReceptorNeuropeptidesObesityOrphanPathologyPathway interactionsPeptide ReceptorPeptidesPertussis ToxinPharmaceutical PreparationsPhosphotransferasesPhysiologicalPhysiologyPlayPublishingQuantitative Reverse Transcriptase PCRReagentReceptor ActivationResearch PersonnelResourcesRewardsRoleRunningScreening ResultSignal TransductionSignaling MoleculeSystemTestingTimeTissuesUnited States National Institutes of HealthVisitaddictionantagonistdesigndrug candidatedrug developmentdrug resourceextracellulargain of functionhigh throughput screeninginsightknock-downloss of functionneuroblastoma cellnew therapeutic targetnoveloverexpressionpeptide hormonereceptorreceptor bindingrecruitscreeningsmall hairpin RNAvalidation studies
项目摘要
Project summary
G protein-coupled receptors (GPCRs) play many important roles in physiology and pathology. GPCRs are the
largest target of FDA approved drugs. Over 100 GPCRs are considered orphans because their endogenous
ligands have not yet been identified, which is necessary for understanding the physiological role of the GPCR
as well as their contribution to CNS disorders. A large fraction of GPCRs are activated by neuropeptides and/or
peptide hormones, and our hypothesis is that many of the orphan receptors are activated by peptides,
presumably novel peptides, because other investigators have screened established bioactive peptides against
orphan receptors. A large number of novel peptides have been identified by peptidomic studies, and functions
for these are not known and hence they are considered ‘orphan peptides’ – these are very likely to function as
bioactive peptides based on their tissue and cellular distribution, localization to the regulatory secretory pathway,
and high sequence conservation across species. Our laboratory has successfully deorphanized six different
orphan peptides in that we identified receptors that are activated by them. In this proposal, we will use a gain-of-
function and a loss of function strategy to identify and validate a larger list of orphan ‘neuropeptide-receptor’
pairs. Our aims are: To identify ‘orphan’ receptors activated by ‘orphan’ neuropeptides using a gain-of-
function strategy (Aim 1), and to validate orphan ‘receptor-neuropeptide’ pairs using secondary screens
including a loss-of-function strategy (Aim 2). In Aim 1 we will use the PRESTO-Tango GPCR kit to screen
orphan GPCRs with orphan peptides. The assay involves overexpression of the GPCRs in the kit in HTLA cells
and measuring peptide-mediated arrestin recruitment. We will screen, 83 validated orphan GPCRs available in
the PRESTO-Tango system with each of the 42 highly curated orphan peptides that fit many of the criteria for
being a bioactive neuropeptide. We have found that several of these peptides cause a rapid and robust increase
in intracellular Ca2+ levels in Neuro 2A neuroblastoma cells and therefore these peptides are excellent candidates
to test against a library of orphan receptors. In Aim 2 we will validate the ‘orphan-neuropeptide’ pairs using
secondary screens as well as with shRNA-mediated knockdown of the target receptor. The identification of
ligands for orphan receptors will provide essential insights into the physiological roles of the receptors as well as
facilitate structural studies investigating receptor-ligand binding sites that are fundamental to the development of
new therapeutics targeting the receptors.
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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Lakshmi A Devi其他文献
エルクサドリンによる止瀉作用におけるMOPr-DOPr ヘテロ二量体の関与.
MOPr-DOPr 异二聚体参与 eluxadoline 的止泻作用。
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:0
- 作者:
藤田和歌子、Ivone Gomes;Lakshmi A Devi - 通讯作者:
Lakshmi A Devi
Lakshmi A Devi的其他文献
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{{ truncateString('Lakshmi A Devi', 18)}}的其他基金
Enhancement of the endogenous opioid system by ketamine
氯胺酮增强内源性阿片系统
- 批准号:
10717708 - 财政年份:2023
- 资助金额:
$ 21.13万 - 项目类别:
Identifying endogenous peptide ligands for orphan G protein-coupled receptors to explore their roles in CNS disorders
鉴定孤儿 G 蛋白偶联受体的内源性肽配体,探索其在中枢神经系统疾病中的作用
- 批准号:
10532036 - 财政年份:2022
- 资助金额:
$ 21.13万 - 项目类别:
Targeted Deorphanization of G Protein-Coupled Receptors
G 蛋白偶联受体的靶向去孤儿化
- 批准号:
9813714 - 财政年份:2019
- 资助金额:
$ 21.13万 - 项目类别:
Post-translational regulation of opioid and cannabinoid receptors
阿片类药物和大麻素受体的翻译后调节
- 批准号:
9249714 - 财政年份:2017
- 资助金额:
$ 21.13万 - 项目类别:
Post-translational regulation of opioid and cannabinoid receptors
阿片类药物和大麻素受体的翻译后调节
- 批准号:
9899230 - 财政年份:2017
- 资助金额:
$ 21.13万 - 项目类别:
Novel approach for developing antibody reagents to probe changes in the synapse p
开发抗体试剂来探测突触 p 变化的新方法
- 批准号:
8522999 - 财政年份:2013
- 资助金额:
$ 21.13万 - 项目类别:
Novel approach for developing antibody reagents to probe changes in the synapse p
开发抗体试剂来探测突触 p 变化的新方法
- 批准号:
8925469 - 财政年份:2013
- 资助金额:
$ 21.13万 - 项目类别:
41st-45th Annual International Narcotics Research Conferences
第 41-45 届年度国际麻醉品研究会议
- 批准号:
8496744 - 财政年份:2010
- 资助金额:
$ 21.13万 - 项目类别:
41st-45th Annual International Narcotics Research Conferences
第 41-45 届年度国际麻醉品研究会议
- 批准号:
8278693 - 财政年份:2010
- 资助金额:
$ 21.13万 - 项目类别:
41st-45th Annual International Narcotics Research Conferences
第 41-45 届年度国际麻醉品研究会议
- 批准号:
8064331 - 财政年份:2010
- 资助金额:
$ 21.13万 - 项目类别:
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