Structure and function of the 5HT2A/mGluR2 complex in schizophrenia
精神分裂症中 5HT2A/mGluR2 复合物的结构和功能
基本信息
- 批准号:7895696
- 负责人:
- 金额:$ 42.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-20 至 2014-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAffinityAgonistAnimal ModelAntipsychotic AgentsAutopsyBehaviorBehavioralBindingBioluminescenceBrainBrain DiseasesCellsChronicClinicalClozapineCo-ImmunoprecipitationsCognitionComplexDevelopmentEmotionsEnergy TransferFluorescenceFluorescence Resonance Energy TransferFutureG-Protein Signaling PathwayG-Protein-Coupled ReceptorsGlutamatesHallucinationsHallucinogensHeterotrimeric GTP-Binding ProteinsHumanIn VitroLinkLysergic Acid DiethylamideMediatingMedicalMental disordersMescalineMolecularMolecular and Cellular BiologyMusNeuronsNeurotransmittersPatientsPatternPerceptionPharmaceutical PreparationsPopulationProcessPsychotic DisordersResearchRoleRouteSchizophreniaSensory ReceptorsSerotoninSerotonin Receptor 5-HT2ASerotonin Receptor 5-HT2CSignal PathwaySignal TransductionSocietiesSpecificityStagingStructureSymptomsSystemValidationatypical antipsychoticbasedrug developmenthippocampal pyramidal neuronin vivometabotropic glutamate receptor 2metabotropic glutamate receptor 3mouse modelneurochemistrynovelpublic health relevancereceptorresearch studyresponse
项目摘要
DESCRIPTION (provided by applicant): One of the guiding objectives of modern schizophrenia research is to build a bridge from molecular and cellular biology to the clinical symptoms of this psychotic mental disorder. Monoaminergic neurotransmitters have been the principal focus of schizophrenia research for many decades. Several approaches have also linked the neurotransmitter glutamate to the neurochemical alterations in patients with schizophrenia. Notably, clozapine and other atypical antipsychotics have high affinity for serotonin 5-HT2A receptors (2AR), and metabotropic glutamate receptors 2/3 (mGluR2/3) agonists have recently shown efficacy in treating schizophrenia. We identify a novel and unexpected functional brain 2AR/mGluR2 receptor complex that may unify the anti- serotonin and glutamatergic therapies of schizophrenia. Our results based on in vitro, animal models and postmortem human brain of schizophrenic subjects suggest that this 2AR/mGluR2 complex may be responsible for some psychotic symptoms in schizophrenia, and that it is the direct target of these two different classes of antipsychotic drugs. In order to understand the role of the 2AR/mGluR2 complex in brain function and to set the stage for future drug development we will pursue two aims. We will use in vitro studies in conjunction with cutting-edge computational approaches to investigate the molecular determinants at the interaction interface responsible for 2AR/mGluR2 complex stabilization and functional crosstalk. In cortical primary cultures and in vivo in mouse models we will study the neuronal signaling and behavior dependent on 2AR/mGluR2 complex function. Results of the proposed studies have the potential to provide a greater understanding of the structure and function of the 2AR/mGluR2 complex than is currently available for any G protein-coupled receptor heterocomplex, and may provide the basis for new pharmacological approaches to the treatment of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a chronic, debilitating psychotic mental disorder that affects about one percent of the population in the U.S.A., and the seventh most costly medical illness to our society. We have discovered a new neuroreceptor complex that induces hallucinations in mouse, and is affected in schizophrenia brain. The characterization of the structure of the neuroreceptor will extend our understanding of the molecular basis of psychosis, and may provide a route to the development of new, more effective drugs for the treatment of schizophrenia.
描述(由申请人提供):现代精神分裂症研究的指导目标之一是建立从分子和细胞生物学到这种精神病性精神障碍临床症状的桥梁。几十年来,单胺类神经递质一直是精神分裂症研究的主要焦点。几种方法也将神经递质谷氨酸与精神分裂症患者的神经化学改变联系起来。值得注意的是,氯氮平和其他非典型抗精神病药物对血清素5-HT2A受体(2AR)具有高亲和力,代谢性谷氨酸受体2/3 (mGluR2/3)激动剂最近显示出治疗精神分裂症的疗效。我们发现了一种新的和意想不到的功能性脑2AR/mGluR2受体复合物,它可能统一抗血清素和谷氨酸能治疗精神分裂症。我们的研究结果基于体外、动物模型和死后的精神分裂症受试者的大脑,表明这种2AR/mGluR2复合体可能是精神分裂症的一些精神病症状的原因,并且它是这两种不同类型的抗精神病药物的直接靶点。为了了解2AR/mGluR2复合物在脑功能中的作用,并为未来的药物开发奠定基础,我们将追求两个目标。我们将使用体外研究结合尖端的计算方法来研究相互作用界面上负责2AR/mGluR2复合物稳定和功能串扰的分子决定因素。在皮质原代培养和小鼠体内模型中,我们将研究依赖于2AR/mGluR2复合物功能的神经元信号传导和行为。这些研究的结果有可能提供对2AR/mGluR2复合物的结构和功能的更深入的了解,而不是目前任何G蛋白偶联受体异复合体,并可能为精神分裂症治疗的新药理学方法提供基础。与公共健康相关:精神分裂症是一种慢性的、使人衰弱的精神病性精神障碍,影响着美国大约1%的人口,是我们社会第七大最昂贵的医疗疾病。我们发现了一种新的神经受体复合物,它能在老鼠身上引起幻觉,并在精神分裂症的大脑中受到影响。神经受体结构的表征将扩展我们对精神病分子基础的理解,并可能为开发新的、更有效的治疗精神分裂症的药物提供一条途径。
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 }}
Javier González-Maeso其他文献
Javier González-Maeso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('Javier González-Maeso', 18)}}的其他基金
Structure and function of the 5HT2A-mGlu2 heteromer in schizophrenia
5HT2A-mGlu2 异聚体在精神分裂症中的结构和功能
- 批准号:
8630649 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
Structure and function of the 5HT2A-mGlu2 heteromer in schizophrenia
5HT2A-mGlu2 异聚体在精神分裂症中的结构和功能
- 批准号:
8813306 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
Structure and function of the 5HT2A-mGlu2 heteromer in schizophrenia
5HT2A-mGlu2 异聚体在精神分裂症中的结构和功能
- 批准号:
9293907 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
Structure and function of the 5HT2A/mGluR2 complex in schizophrenia
精神分裂症中 5HT2A/mGluR2 复合物的结构和功能
- 批准号:
7728021 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
Structure and function of GPCR heteromeric complexes in brain
脑内GPCR异聚复合物的结构和功能
- 批准号:
10252884 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
Structure and function of the 5HT2A/mGluR2 complex in schizophrenia
精神分裂症中 5HT2A/mGluR2 复合物的结构和功能
- 批准号:
8267620 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
Structure and function of the 5HT2A/mGluR2 complex in schizophrenia
精神分裂症中 5HT2A/mGluR2 复合物的结构和功能
- 批准号:
8433427 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
Structure and function of GPCR heteromeric complexes in brain
脑内GPCR异聚复合物的结构和功能
- 批准号:
10685601 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
Structure and function of the 5HT2A/mGluR2 complex in schizophrenia
精神分裂症中 5HT2A/mGluR2 复合物的结构和功能
- 批准号:
8063085 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
Structure and function of GPCR heteromeric complexes in brain
脑内GPCR异聚复合物的结构和功能
- 批准号:
10445344 - 财政年份:2009
- 资助金额:
$ 42.38万 - 项目类别:
相似海外基金
Discovery of a High Affinity, Selective and β-arrestin Biased 5-HT7R Agonist
发现高亲和力、选择性和β-抑制蛋白偏向的 5-HT7R 激动剂
- 批准号:
10412227 - 财政年份:2022
- 资助金额:
$ 42.38万 - 项目类别:
Discovery of a High Affinity, Selective and β-arrestin Biased 5-HT7R Agonist
发现高亲和力、选择性和β-抑制蛋白偏向的 5-HT7R 激动剂
- 批准号:
10610473 - 财政年份:2022
- 资助金额:
$ 42.38万 - 项目类别:
Supplement to Discovery of a high affinity, selective and beta-arrestinbiased 5-HT7R Agonist Grant
对高亲和力、选择性和 β 抑制偏向 5-HT7R 激动剂发现的补充补助金
- 批准号:
10799162 - 财政年份:2022
- 资助金额:
$ 42.38万 - 项目类别:
NMDA RECEPTOR--AGONIST AFFINITY, EFFICACY/TRANSDUCTION
NMDA 受体——激动剂亲和力、功效/转导
- 批准号:
6639179 - 财政年份:2001
- 资助金额:
$ 42.38万 - 项目类别:
NMDA RECEPTOR--AGONIST AFFINITY, EFFICACY/TRANSDUCTION
NMDA 受体——激动剂亲和力、功效/转导
- 批准号:
6724797 - 财政年份:2001
- 资助金额:
$ 42.38万 - 项目类别:
General Anesthetics and nAcCHOR Agonist Affinity
全身麻醉药和 nAcCHOR 激动剂亲和力
- 批准号:
6636512 - 财政年份:2001
- 资助金额:
$ 42.38万 - 项目类别:
General Anesthetics and nAcCHOR Agonist Affinity
全身麻醉药和 nAcCHOR 激动剂亲和力
- 批准号:
6326889 - 财政年份:2001
- 资助金额:
$ 42.38万 - 项目类别:
NMDA RECEPTOR--AGONIST AFFINITY, EFFICACY/TRANSDUCTION
NMDA 受体——激动剂亲和力、功效/转导
- 批准号:
6266928 - 财政年份:2001
- 资助金额:
$ 42.38万 - 项目类别:
NMDA RECEPTOR--AGONIST AFFINITY, EFFICACY/TRANSDUCTION
NMDA 受体——激动剂亲和力、功效/转导
- 批准号:
6539099 - 财政年份:2001
- 资助金额:
$ 42.38万 - 项目类别:
General Anesthetics and nAcCHOR Agonist Affinity
全身麻醉药和 nAcCHOR 激动剂亲和力
- 批准号:
6520329 - 财政年份:2001
- 资助金额:
$ 42.38万 - 项目类别: