Molecular determinants for the action of psychostimulants

精神兴奋剂作用的分子决定因素

• 批准号: 8911290
• 负责人: Jonathan A Javitch
• 金额: $ 12.96万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911290
• 关键词: Agonist; Amphetamines; Antipsychotic Agents; Arrestins; Award; Behavioral; Binding; Biological Models; Biology; Biophysics; Catecholamines; Cell physiology; Cells; Chemicals; Cocaine; Collaborations; Computer Analysis; Crystallography; Data; Development; Dopamine; Dopamine Receptor; Drug abuse; Drug effect disorder; Electron Spin Resonance Spectroscopy; Emotional; Faculty; Family; Fluorescence Spectroscopy; Fostering; Functional disorder; Funding; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Grant; Growth; Homologous Gene; Image; Institutes; Internet; Journals; K-Series Research Career Programs; Laboratories; Laboratory Study; Life; Manuscripts; Membrane Proteins; Mental disorders; Mentors; Mentorship; Methods; Molecular; Molecular Biology; Molecular Probes; Molecular Target; Mus; Nature; Neurosciences; Neurotransmitters; New York; Opioid Receptor; Peer Review; Pharmacology; Physicians; Physiological; Play; Process; Property; Proteins; Psychiatry; Publications; Publishing; Regulation; Research; Research Methodology; Rewards; Role; Science; Senior Scientist Award; Signal Transduction; Specificity; Structure; Structure-Activity Relationship; Students; Substance abuse problem; Surgeon; System; Therapeutic; Time; United States National Academy of Sciences; United States National Institutes of Health; Universities; Work; base; career; career development; cognitive reappraisal; college; dopamine transporter; drug of abuse; flexibility; fly; inhibitor/antagonist; insight; medical specialties; member; molecular recognition; nervous system disorder; novel; novel strategies; professor; programs; protein activation; psychostimulant; receptor; reuptake; single molecule; structural biology; transmission process

DESCRIPTION (provided by applicant): The catecholamine dopamine (DA) plays a key role in the regulation of cognitive, emotional, and behavioral functions. Abnormalities in its regulation have been implicated in drug abuse as well as several psychiatric and neurological disorders. DA exerts it actions at D2-like and D1-like receptors, members of the G protein-coupled receptor (GPCR) family. DA reuptake by the DA transporter (DAT) is a principal mechanism for terminating dopaminergic transmission, and this protein is the primary molecular target of amphetamine, cocaine, and other psychostimulants. The Javitch laboratory studies structure-function relationships and mechanisms of regulation of neurotransmitter transporters and related bacterial transporters, as well as mechanisms of dopamine receptor oligomerization and function. His long-term research goals are to: 1) Understand the structural bases of agonist and antagonist binding and specificity in G protein-coupled receptors, with a current focus on DA and opioid receptors. 2) Determine how agonist binding is transduced into G-protein activation and arrestin recruitment and signaling. 3) Determine the structural bases of substrate translocation and inhibitor binding to neurotransmitter transporters and the dynamics associated with transport using biophysical and structural approaches in parallel with computational analysis. 4) Determine the mechanistic bases of AMPH-induced DA efflux and the role of regulation of these processes in sensitization and substance abuse. The K Award enables the candidate to devote focused effort to the exploration of new approaches, novel systems and various multi-disciplinary methods and collaborations aimed at one of the central goals of the research program in the laboratory - the mechanisms of drugs of abuse. The candidate's laboratory is pursuing membrane protein crystallography and electron paramagnetic resonance & single molecule fluorescence spectroscopy of bacterial homologs of neurotransmitter transporters. This work is now being extended to single molecule imaging of receptors in living cells. The lab is also pursuing work in genetically modified flies and mice as model systems to probe molecular and mechanistic insights in a physiological background. These new approaches are being developed and used to maintain the candidate's research at the leading edge of the field of molecular mechanisms of drug abuse and actions of antipsychotic drugs. The support of the K05 Award would play an essential role in the candidate's continued growth by giving him the flexibility to focus on expanding his research methodologies and to fuse his own professional growth with that of his research program as well as extensive mentorship of his trainees and junior faculty.

描述（由申请人提供）：儿茶酚胺多巴胺（DA）在认知、情感和行为功能的调节中起关键作用。在其监管方面的不当行为与药物滥用以及几种精神和神经疾病有关。DA作用于D2样和D1样受体，即G蛋白偶联受体（GPCR）家族成员。DA转运蛋白（DAT）的DA重摄取是终止多巴胺能传递的主要机制，该蛋白是苯丙胺、可卡因和其他精神兴奋剂的主要分子靶点。Javitch实验室研究神经递质转运蛋白和相关细菌转运蛋白的结构-功能关系和调节机制，以及多巴胺受体寡聚化和功能的机制。他的长期研究目标是：1）了解G蛋白偶联受体中激动剂和拮抗剂结合和特异性的结构基础，目前重点是DA和阿片受体。2)确定激动剂结合如何被转换成G蛋白激活和抑制蛋白募集和信号传导。3)确定底物易位和抑制剂结合到神经递质转运蛋白的结构基础，以及使用生物物理和结构方法与计算分析并行的与运输相关的动力学。4)确定AMPH诱导的DA外排的机制基础以及这些过程在致敏和物质滥用中的调节作用。K奖使候选人能够专注于探索新方法，新系统和各种多学科方法以及旨在实验室研究计划的中心目标之一的合作-滥用药物的机制。候选人的实验室正在进行膜蛋白晶体学和电子顺磁共振和神经递质转运蛋白的细菌同系物的单分子荧光光谱学。这项工作现在正在扩展到活细胞中受体的单分子成像。该实验室还在进行转基因苍蝇和小鼠的研究，作为在生理背景下探索分子和机制见解的模型系统。这些新的方法正在开发和使用，以保持候选人的研究在药物滥用和抗精神病药物的作用的分子机制领域的前沿。K 05奖的支持将在候选人的持续成长中发挥至关重要的作用，使他能够灵活地专注于扩大他的研究方法，并将自己的专业成长与他的研究计划以及他的学员和初级教师的广泛指导相融合。