Molecular Determinants for the Action of Psychostimulants

精神兴奋剂作用的分子决定因素

基本信息

批准号：
7319355
负责人：
Jonathan A Javitch
金额：
$ 12.31万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7319355
关键词：
Achievement Acute Address Adrenergic Receptor Affect Affinity Labels Agonist Amino Acids Amphetamines Antibodies Antidepressive Agents Antipsychotic Agents Archaeal Genome Area Aromatic Amino Acids Aspartate Atomic Force Microscopy Award Basic Science Behavior Behavioral Benztropine Binding Binding Sites Biochemical Biogenic Amine Receptors Biological Assay Biological Models Catecholamines Cells Charge Choline Chromatography Chronic Class Cleaved cell Cocaine Cognitive Collaborations Complex Condition Consensus Consensus Sequence Controlled Study Cryoelectron Microscopy Crystallization Crystallography Cultured Cells Cyclophosphamide/Fluorouracil/Prednisone Cysteine D Aspartate DNA Sequence Rearrangement DRD2 gene Data Detergents Development Dimerization Distal Disulfides Diving Dopamine Dopamine Agonists Dopamine D2 Receptor Dopamine Receptor Dose Drug abuse Electron Spin Resonance Spectroscopy Emotional Endopeptidases Engineering Environment Epitopes Escherichia coli Exhibits Face Family Fluorescence Resonance Energy Transfer Fluorescence Spectroscopy Fusobacterium nucleatum G-Protein-Coupled Receptors GTP-Binding Proteins Genes Germ Cells Goals Grant Growth Heterodimerization Higher Order Chromatin Structure Homo Homologous Gene Homology Modeling Hybrids IL3 gene In Vitro Indium Individual Integral Membrane Protein Interleukin-1 Intracellular Transport Ions Journals K-Series Research Career Programs Knock-in Mouse Label Laboratories Laboratory Study Lactococcus lactis Length Leucine Ligand Binding Ligands Link Location Manuscripts Maps Mass Spectrum Analysis Measurement Measures Mediating Membrane Membrane Proteins Metals Methodology Methods Modeling Molecular Molecular Conformation Molecular Probes Molecular Sieve Chromatography Molecular Structure Molecular Target Morphologic artifacts Movement Mus Mutation N(delta)-acetylornithine, -isomer N-dodecanoylglutamic acid, -isomer, sodium salt N-terminal Nature Neurons Neurotransmitters Norepinephrine Notification Numbers Opioid Receptor Organism Orphan Pathway interactions Pattern Peptide Hydrolases Pharmaceutical Preparations Phospho-Specific Antibodies Phosphorylation Phosphorylation Site Phosphotransferases Physiological Play Pliability Positioning Attribute Predisposition Preparation Principal Investigator Process Property Protein Binding Protein Overexpression Proteins Proteomics Protomer Publications Publishing Quinpirole Receptor Activation Recombinants Regulation Research Resistance Resolution Rewards Rhodopsin Role SSTR5 gene Screening procedure Senior Scientist Award Serine Side Signal Transduction Simulate Site Sodium Somatostatin Specificity Squid Stable Isotope Labeling Staging Structure Structure-Activity Relationship Sulfhydryl Reagents Sulpiride Surface Synapses Synaptic Cleft System Testing Time Tissues Tracer Transgenic Mice Tropanes Tryptophan Tyrosine Universities Vesicle Work Writing Yeasts addiction affinity labeling alpha-difluoromethyl-DOPA, -isomer alpha-methylornithine dihydrochloride, -isomer analog base calmodulin-dependent protein kinase II combinatorial crosslink design dimer dopamine D4 receptor dopamine transporter dopaminergic neuron drug of abuse experience extracellular fly human DRD4 protein in vivo inhibitor/antagonist insight member monomer multidisciplinary mutant nervous system disorder novel novel strategies prevent programs protein activation proteoliposomes psychostimulant receptor receptor function reconstitution research study response reuptake serotonin transporter single molecule small molecule small molecule libraries sodium ion somatostatin receptor 5 syntaxin 1 synthetic peptide time use transmission process tryptophan analog uptake water channel

项目摘要

DESCRIPTION (provided by applicant): The catecholamine dopamine (DA) plays a key role in the regulation of cognitive, emotional, and behavioral functions, and abnormalities in its regulation have been implicated in 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 relations 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 dopamine and opioid receptors. 2) Determine how agonist binding is transduced into G-protein activation. 3) Determine the structural bases of substrate translocation and inhibitor binding to the dopamine transporter. 4) Determine the mechanistic bases of amphetamine-induced dopamine efflux and the role of regulation of these processes in sensitization. The K Award enables the candidate to devote focused efforts to the exploration of new approaches, novel systems and various multidisciplinary methods and collaborations aimed at one of the central goals of the research program in the laboratory - the mechanisms of drugs of abuse. In collaboration with leading experts, individuals in the candidate's laboratory are now pursuing membrane protein crystallography and electron paramagnetic resonance & single molecule fluorescence spectroscopy of bacterial homologs of neurotransmitter transporter and are also pursuing work in knock-in mice and transgenic flies as model systems to probe molecular and mechanistic insights in a physiological background. These new approaches are being developed and used to lay the groundwork 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 in part outside of the area of his current methodologies and to fuse his own professional growth with that of his research program and his trainees.

描述（由申请人提供）：儿茶酚胺多巴胺（DA）在认知、情绪和行为功能的调节中发挥着关键作用，其调节异常与多种精神和神经疾病有关。 DA 对 D2 样和 D1 样受体（G 蛋白偶联受体 (GPCR) 家族的成员）发挥作用。 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，该蛋白是安非他明、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) 了解激动剂和拮抗剂结合的结构基础以及 G 蛋白偶联受体的特异性，目前的重点是多巴胺和阿片受体。 2) 确定激动剂结合如何转导为 G 蛋白激活。 3) 确定底物易位和抑制剂与多巴胺转运蛋白结合的结构基础。 4) 确定安非他明诱导的多巴胺流出的机制基础以及这些过程在致敏中的调节作用。 K 奖使候选人能够集中精力探索新方法、新颖系统以及各种多学科方法和合作，以实现实验室研究项目的中心目标之一——药物滥用机制。候选人实验室的人员与顶尖专家合作，目前正在研究神经递质转运蛋白细菌同系物的膜蛋白晶体学、电子顺磁共振和单分子荧光光谱学，并且还在以基因敲入小鼠和转基因果蝇为模型系统进行探索。生理背景下的分子和机制见解。这些新方法的开发和使用是为了奠定基础，以保持候选人的研究在药物滥用分子机制和抗精神病药物作用领域的领先地位。 K05 奖的支持将为候选人的持续成长发挥重要作用，让他能够灵活地专注于当前方法论领域之外的部分，并将自己的专业成长与他的研究项目和学员的专业成长融合起来。