Dynorphins and Kappa Opioid Receptors in the Stress Response

描述（由申请人提供）： 这是一份高级科学家K 05奖的申请书，用于Charles Chavkin博士的研究职业发展，他是华盛顿大学药理学系疼痛研究的Allan和Phyllis Treuer主席。Chavkin博士在斯坦福大学接受了药理学博士培训，在加入华盛顿大学之前在索尔克研究所和斯克里普斯诊所完成了博士后培训。他目前是RO 1-DA 11672 -06、R 01-DA 16898 -02、P01-DA 15916 -03的主要研究者和T32-DA 07278 -11的负责人。这些赠款的研究目的分别是：1）研究Kir 3型钾通道阿片受体激活的磷酸化调节机制，2）研究行为应激诱导可卡因奖赏增强的细胞机制，3）利用转基因小鼠模型研究阿片镇痛耐受的机制，和4）监督药物滥用研究分子方法的博士前和博士后研究员的培训。此K 05申请的目的是巩固对Chavkin博士的工资支持，并减少其非研究相关的行政责任。该计划得到了药理学系主任和医学院研究副院长的全力支持。该研究计划的长期目标是进一步发展多学科方法来研究内源性强啡肽阿片类神经肽在药物成瘾中的作用。强啡肽/κ阿片样物质系统似乎是慢性应激反应的关键介质，其作用方式增强了可卡因的奖励特性。了解慢性压力如何增加吸毒成瘾的风险并增加复发的风险具有重要的治疗意义。解决这些问题所需的多学科方法需要分子生物学工具来定义药物作用的靶点，分子药理学方法来解决反应背后的细胞事件，电生理学方法来定义药物对受影响神经元的作用，解剖学方法来定义神经回路和药物作用部位，和行为方法，以提供相关的和有效的刺激神经系统。该奖项将大大加强候选人在这一综合努力中发挥领导作用的能力。

DESCRIPTION (provided by applicant): This is an application for a Senior Scientist K05 award for the research career development of Dr. Charles Chavkin who is the Allan and Phyllis Treuer Chair of Pain Research in the Department of Pharmacology at the University of Washington. Dr. Chavkin received his PhD training in pharmacology at Stanford University, completed postdoctoral training at the Salk Institute and Scripps Clinic before joining the faculty at the University of Washington. He is currently the principal investigator of RO1-DA11672-06, R01-DA16898-02, P01-DA15916-03, and director of T32-DA07278-11. The research aims of these grants are respectively designed to 1) study the phosphorylation mechanisms regulating of opioid receptor activation of Kir3 type potassium channels, 2) study the cellular mechanisms responsible for behavioral stress-induced potentiation of the cocaine reward, 3) study the mechanisms of opioid analgesic tolerance using transgenic mouse models, and 4) supervise training of predoctoral and postdoctoral fellows in molecular approaches of drug abuse research. The purpose of this K05 application is to consolidate salary support for Dr. Chavkin and to reduce his non-research related administrative responsibilities. This plan has the full support of the department of pharmacology Chair and the Vice-Dean for Research in the School of Medicine. The long term goals of the proposed research plan are to further develop a multidisciplinary approach to the study of the actions of endogenous dynorphin opioid neuropeptides in drug addiction. The dynorphin/kappa opioid system seems to function as key mediators of the response to chronic stress in ways that potentiate the rewarding properties of cocaine. Understanding how chronic stress increases the risk of drug addiction and increases the risk of relapse has important therapeutic implications. The multidisciplinary approach necessary to address these questions requires molecular biological tools to define the targets of drug action, molecular pharmacological methods to resolve the cellular events underlying the responses, electrophysiological methods to define the actions of drugs on the neurons affected, anatomical methods to define the neural circuits and sites of drug action, and behavioral methods to provide relevant and valid stimuli to the nervous system. The award would greatly strengthen the candidate's ability to provide leadership in this integrative effort.