Dynorphins and Kappa Opioid Receptors in the Stress Response

应激反应中的强啡肽和 Kappa 阿片受体

基本信息

批准号：
8189425
负责人：
Charles Chavkin
金额：
$ 12.23万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8189425
关键词：
Absence of pain sensation Acute Adverse effects Analgesics Analytical Chemistry Arrestins Award Behavioral Biomedical Research Brain Brain region Cell membrane Cocaine Collaborations Community Outreach Complex Development Disease Drug Addiction Drug abuse Dynorphins Educational process of instructing Electrodes Event Excision Extramural Activities Faculty Fellowship Fostering Foundations Funding G Protein-Coupled Receptor Signaling GRK Gene Expression Goals Grant Image International JUN gene Kinetics Knock-out Knockout Mice Leadership MAP Kinase Gene MAPK14 gene MAPK9 gene Measures Mediating Mentors Mentorship Metabolic Clearance Rate Methods Molecular Mood Disorders Morphine Mus Mutate Narcotics National Institute of Drug Abuse Neurons Opioid Opioid Receptor Pain Peer Review Pharmacology Phosphotransferases Physiological Positioning Attribute Postdoctoral Fellow Prosencephalon Proteins Proteomics Publications Publishing Receptor Activation Receptor Signaling Regulation Request for Applications Research Resolution Risk Role Scanning Schedule Senior Scientist Senior Scientist Award Serotonin Services Signal Transduction Stress Students Swimming Synaptosomes System Techniques Testing Therapeutic Time Training Training Programs Work addiction biological adaptation to stress cell type classical conditioning desensitization dorsal raphe nucleus drug of abuse graduate student insight kappa opioid receptors member mu opioid receptors neural circuit novel novel strategies professor programs promoter ranpirnase recombinase research facility research study response restoration reuptake serotonin transporter stress resilience symposium

项目摘要

DESCRIPTION (provided by applicant): This is a first renewal application requesting a second 5-yr period of support of a Senior Scientist Research and Mentorship Award (K05). The current award has been extremely important for my professional development as a scientific leader and mentor by allowing me to focus my effort on those responsibilities. My scientific leadership efforts during this period include direction of a UW Center for Drug Addiction Research, developing core behavioral, imaging and proteomic research facilities, fostering scientific collaborations, and promoting community outreach. My extramural leadership includes organization of a scientific conference scheduled in July 2011 on the "Therapeutic Potential of Kappa Opioids in Pain and Addiction" and service on the executive committees of the International Narcotics Research Conference (INRC). The current K05 award has enabled me to focus my effort on research progress and has resulted in 28 peer-reviewed publications during the last 4+ years that incorporated new approaches, generated new insights, and developed novel hypotheses. The current funding period has supported an expansion of my mentorship activities including the renewal of a NIDA T32 "Training in Molecular Pharmacology of Abused Drugs" and the award of an ARRA-NIDA P30 "New Faculty Search For Functional Proteomic Approaches To Drug Abuse," both of which I direct. The K05, P30 and T32 awards have encouraged my active participation in a "Biomedical Research Integrity Training Program" and enabled active mentoring of graduate and undergraduate students, postdoctoral fellows, and new faculty. The next period of K05 support would build on this foundation by protecting my time from extra service-teaching and administrative responsibilities and allowing me to devote my efforts towards 3 research goals: First, to test the hypothesis that opioid receptor activation of c-Jun Kinase provides a novel mechanism of GPCR signal regulation. Second, that kappa opioid receptor activation of p38 MAPK initiates signaling events responsible for the dysphoric and anxiogenic effects of stress. And third, in the next period of support, the K05 would enable my lab to gain strength in protein analytical chemistry techniques necessary to define components of the opioid receptor signaling complex. In the current funding period, I have mentored 3 postdoctoral fellows who have gone on to faculty positions (Bruchas, Macey & Gendron); 2 junior faculty members who have built successful research programs and earned promotion (Phillips and Stella); and 3 graduate students who earned their doctorates and advanced to postdoctoral fellowship positions. In the next funding period, I expect to actively promote the professional development of two new tenure-track assistant professors (Zwiefel and Ong), 5 graduate students & 3 postdoctoral fellows currently working in the lab. PUBLIC HEALTH RELEVANCE: Although the stress response is generally protective, repeated and uncontrollable stress exposure can increase the risks of mood disorders and drug addiction. The mechanisms underlying these adverse effects need to be understood before better treatments for stress-related diseases can be developed. Activation of the dynorphin/kappa opioid systems in brain has been shown to encode the dysphoric effects of stress, and kappa receptor antagonism has been shown to promote stress-resilience. The proposed studies would increase our understanding of these effects and would promote the development of novel treatments for addiction and mood disorders.

描述（由申请人提供）：这是第一个续签申请，要求对高级科学家研究与指导奖（K05）的第二次支持。目前的奖项对于我作为科学领导者和导师的专业发展非常重要，因为我可以将自己的精力集中在这些责任上。在此期间，我的科学领导力努力包括UW药物成瘾研究中心的方向，发展核心行为，成像和蛋白质组学研究设施，促进科学合作以及促进社区外展。我的校外领导包括安排在2011年7月举行的科学会议，该会议于2011年7月举行，涉及“卡帕阿片类药物在疼痛和成瘾中的治疗潜力”以及在国际麻醉品研究会议（INRC）执行委员会上的服务。当前的K05奖使我能够将自己的努力集中在研究进度上，并在过去的4年以上导致了28个同行评审的出版物，并结合了新的方法，产生了新的见解并开发了新颖的假设。目前的资金期支持了我的指导活动的扩展，包括续签NIDA T32“滥用药物的分子药理学培训”，以及授予Arra-NIDA P30“新的教师”的新教师，以寻求用于吸毒的功能性蛋白质组学方法，这两种方法都是我指导的。 K05，P30和T32奖项鼓励我积极参与“生物医学研究完整性培训计划”，并能够积极地指导研究生和本科生，博士后研究员和新教师。下一个K05的支持将通过保护我的时间免受额外的服务和行政责任的基础，并让我将自己的努力投入到3个研究目标上：首先，测试阿片类药物受体激活C-JUN激酶的假设提供了GPCR信号法规的新型机制。其次，p38 MAPK的Kappa阿片受体激活启动了负责压力烦躁和焦虑作用的信号事件。第三，在下一阶段的支持中，K05将使我的实验室能够获得定义阿片类药物受体信号传导复合物成分所需的蛋白质分析化学技术的强度。在当前的资金期间，我指导了3名博士后研究员（Bruchas，Macey＆Gendron）； 2名建立了成功的研究计划并获得晋升的初级教职员工（Phillips和Stella）；还有3名获得博士学位并晋升为博士后奖学金职位的研究生。在下一个资金期间，我希望积极促进两位新的终身助理教授（Zwiefel和Ong），5名研究生和3名目前在实验室工作的博士后研究员的专业发展。公共卫生相关性：尽管压力反应通常具有保护性，但重复和无法控制的压力暴露会增加情绪障碍和吸毒的风险。在建立更好的与压力相关疾病的治疗方法之前，需要了解这些不良反应的基础机制。已经证明，大脑中的动酚/kappa阿片类药物的激活可以编码压力的烦躁作用，而Kappa受体拮抗作用已被证明可以促进胁迫缓解能力。拟议的研究将增加我们对这些影响的理解，并将促进成瘾和情绪障碍的新型治疗方法的发展。