Molecular determinants for the action of psychostimulants

描述(申请人提供)：儿茶酚胺多巴胺(DA)在调节认知、情绪和行为功能方面起着关键作用。其监管的异常被认为与药物滥用以及几种精神和神经疾病有关。DA作用于G蛋白偶联受体家族中的D2样受体和D1样受体。DA转运体(DAT)的DA再摄取是终止多巴胺能传递的主要机制，该蛋白是苯丙胺、可卡因和其他精神刺激剂的主要分子靶点。贾维奇实验室研究神经递质转运体和相关细菌转运体的结构-功能关系和调节机制，以及多巴胺受体寡聚和功能的机制。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的结构基础和特异性，目前的重点是DA和阿片受体。2)确定激动剂结合如何转化为G蛋白激活、arrestin募集和信号传递。3)利用生物物理和结构方法，结合计算分析，确定底物转运体和神经递质转运体结合抑制剂的结构基础以及与转运体相关的动力学。4)确定Amph诱导DA外流的机制基础，以及这些过程在敏化和物质滥用中的调节作用。K奖使候选人能够集中精力探索新的途径、新的系统以及各种多学科方法和合作，旨在实现实验室研究计划的中心目标之一--药物滥用机制。候选人的实验室正在研究膜蛋白结晶学和电子顺磁共振&神经递质转运体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。该实验室还在利用转基因果蝇和小鼠作为模型系统，探索生理背景下的分子和机械洞察。这些新的方法正在开发和使用，以保持候选人在药物滥用和抗精神病药物作用的分子机制领域的前沿研究。K05奖的支持将对候选人的持续成长起到至关重要的作用，使他能够灵活地专注于扩展他的研究方法，并将他自己的专业成长与他的研究计划的专业成长以及对他的受训者和初级教师的广泛指导相结合。 公共卫生相关性：K05高级科学家奖将支持一位知名教授的持续职业发展和指导活动，他的实验室专注于了解受体和转运体的结构、功能和调节，以及它们在药物滥用的病理生理学和潜在疗法中的作用。

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. PUBLIC HEALTH RELEVANCE: This K05 Senior Scientist Award would support the continued career development and mentorship activities of an established Professor whose laboratory focuses on understanding the structure, function, and regulation of receptors and transporters and their role in the pathophysiology and potential therapeutics of drug abuse.