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.
项目摘要
G蛋白偶联受体(GPCRs)在生理和病理学中起着重要作用。GPCR是
FDA批准药物的最大目标。超过100个GPCR被认为是孤儿,因为它们的内源性
配体尚未被鉴定,这对于理解GPCR的生理作用是必要的
以及它们对CNS疾病的贡献。大部分GPCR被神经肽和/或神经肽受体激活。
肽激素,我们的假设是许多孤儿受体被肽激活,
可能是新的肽,因为其他研究人员已经筛选了建立的生物活性肽,
孤儿受体通过肽组学研究和功能鉴定了大量新型肽
因为这些肽是未知的,因此它们被认为是“孤儿肽”-这些肽很可能作为
生物活性肽基于它们的组织和细胞分布,定位于调节分泌途径,
和物种间的高度序列保守性。我们的实验室已经成功地将六种不同的
孤儿肽,因为我们鉴定了被它们激活的受体。在本建议中,我们将使用增益-
功能和功能丧失策略,以鉴定和验证孤儿“神经肽受体”的更大列表
对.我们的目标是:通过使用增益的方法来识别由“孤儿”神经肽激活的“孤儿”受体,
功能策略(目标1),并使用二次筛选验证孤儿“受体-神经肽”对
包括功能丧失策略(目标2)。在目标1中,我们将使用PRESTO-Tango GPCR试剂盒进行筛选
具有孤儿肽的孤儿GPCR。该测定涉及试剂盒中GPCR在HTLA细胞中的过表达
和测量肽介导的抑制蛋白募集。我们将筛选83个经验证的孤儿GPCR,
PRESTO-Tango系统具有42种高度精选的孤儿肽,符合许多标准,
是一种生物活性神经肽。我们已经发现,这些肽中的几种引起快速和强烈的增加,
在Neuro 2A神经母细胞瘤细胞中的细胞内Ca 2+水平,因此这些肽是极好的候选物
来测试孤儿受体库在目标2中,我们将使用
二次筛选以及shRNA介导的靶受体敲低。的识别
孤儿受体的配体将提供对受体的生理作用以及
促进结构研究,研究受体-配体结合位点,这对发展
针对受体的新疗法。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似国自然基金
Agonist-GPR119-Gs复合物的结构生物学研究
- 批准号:32000851
- 批准年份:2020
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
相似海外基金
S1PR1 agonistによる脳血液関門制御を介した脳梗塞の新規治療法開発
S1PR1激动剂调节血脑屏障治疗脑梗塞新方法的开发
- 批准号:
24K12256 - 财政年份:2024
- 资助金额:
$ 21.13万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
AHR agonistによるSLE皮疹の新たな治療薬の開発
使用 AHR 激动剂开发治疗 SLE 皮疹的新疗法
- 批准号:
24K19176 - 财政年份:2024
- 资助金额:
$ 21.13万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Evaluation of a specific LXR/PPAR agonist for treatment of Alzheimer's disease
特定 LXR/PPAR 激动剂治疗阿尔茨海默病的评估
- 批准号:
10578068 - 财政年份:2023
- 资助金额:
$ 21.13万 - 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
- 批准号:
10933287 - 财政年份:2023
- 资助金额:
$ 21.13万 - 项目类别:
Targeting breast cancer microenvironment with small molecule agonist of relaxin receptor
用松弛素受体小分子激动剂靶向乳腺癌微环境
- 批准号:
10650593 - 财政年份:2023
- 资助金额:
$ 21.13万 - 项目类别:
AMPKa agonist in attenuating CPT1A inhibition and alcoholic chronic pancreatitis
AMPKa 激动剂减轻 CPT1A 抑制和酒精性慢性胰腺炎
- 批准号:
10649275 - 财政年份:2023
- 资助金额:
$ 21.13万 - 项目类别:
Investigating mechanisms underpinning outcomes in people on opioid agonist treatment for OUD: Disentangling sleep and circadian rhythm influences on craving and emotion regulation
研究阿片类激动剂治疗 OUD 患者结果的机制:解开睡眠和昼夜节律对渴望和情绪调节的影响
- 批准号:
10784209 - 财政年份:2023
- 资助金额:
$ 21.13万 - 项目类别:
A randomized double-blind placebo controlled Phase 1 SAD study in male and female healthy volunteers to assess safety, pharmacokinetics, and transient biomarker changes by the ABCA1 agonist CS6253
在男性和女性健康志愿者中进行的一项随机双盲安慰剂对照 1 期 SAD 研究,旨在评估 ABCA1 激动剂 CS6253 的安全性、药代动力学和短暂生物标志物变化
- 批准号:
10734158 - 财政年份:2023
- 资助金额:
$ 21.13万 - 项目类别:
A novel nanobody-based agonist-redirected checkpoint (ARC) molecule, aPD1-Fc-OX40L, for cancer immunotherapy
一种基于纳米抗体的新型激动剂重定向检查点 (ARC) 分子 aPD1-Fc-OX40L,用于癌症免疫治疗
- 批准号:
10580259 - 财政年份:2023
- 资助金额:
$ 21.13万 - 项目类别:
Identification and characterization of a plant growth promoter from wild plants: is this a novel plant hormone agonist?
野生植物中植物生长促进剂的鉴定和表征:这是一种新型植物激素激动剂吗?
- 批准号:
23K05057 - 财政年份:2023
- 资助金额:
$ 21.13万 - 项目类别:
Grant-in-Aid for Scientific Research (C)