Administrative Core

行政核心

基本信息

批准号：
7612851
负责人：
HORACE LOH
金额：
$ 26.49万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7612851
关键词：
AMPA Receptors Accounting Address Analgesics Animals Award Basic Science Behavior Behavioral Biochemical Budgets Cellular biology Clinical Treatment Clonidine Collaborations Commit Corpus striatum structure Data Dendritic Spines Dependence Development Drug Addiction Drug effect disorder Education Electrophysiology (science)Excitatory Synapse Exhibits Faculty Fostering Funding General Population Genetic Transcription Goals Grant Group Meetings Head Individual International Investigation K-Series Research Career Programs Laws Legal patent Manuscripts Mind Minnesota Mission Molecular Mus Mutation Narcotics National Institute of Drug Abuse Nature Neurons Neuropharmacology Neurosciences Opiate Addiction Opiates Opioid Opioid Receptor Participant Pharmaceutical Preparations Pharmacology Plasmids Postdoctoral Fellow Problem Solving Process Progress Reports Proteins RGS Proteins Reagent Receptor Signaling Records Recruitment Activity Regulation Research Research Personnel Research Project Grants Resources Role Scientist Seeds Senior Scientist Award Severities Signal Transduction Source Structure Synaptic Transmission Synaptic plasticity System Training Training and Education Transcriptional Regulation Translating Universities Withdrawal Work addiction base chronic pain clinical application computerized data processing drug mechanism innovation interdisciplinary approach interest investigator training member multidisciplinary mutant neuroimmunology opiate alkaloid outreach programs protein function receptor relating to nervous system success symposium synergism trafficking

项目摘要

Our Center, the Basic Research Center on Molecular and Cell Biology of Drug Addiction (MCBDA, www.MCBDA.ahc.umn.edu), was established 10 years ago with the mission of developing treatments for drug addiction by understanding the mechanisms of drug actions, via basic research. We had 4 objectives when we established the Center: (1) to foster interdisciplinary approaches in drug addiction research; 2) to serve as an "activity" Center in coordinating and promoting all academic and scholarly activities on drug addiction research at University of Minnesota; 3) to serve as a national resource for molecular and cell biology of drug addiction research; and 4) to serve as training Center for young scientists at the University of Minnesota. Thus far, we have been successful in accomplishing many aspects of these objectives. With 8 scientific components and an Administrative Core constituting the structure of Center during the last funding period, and due to the diversity and breath in the research interests of the faculty involved, the Center has established itself as a productive training ground for young scientists interested in drug addiction research. As summarized in our discussion of the Seed Grant Program in the Training and Education section (page 55), the Center has funded some innovative research projects submitted by young scientists. Two of the Seed Grant awardees, Dr. Dezhi Liao (Department of Neuroscience) and Dr. Kirill Martemyanov (Department of Pharmacology), used the results generated with Center support to successfully compete for R01 research awards aimed at: 1) the study of opioid regulation of dendritic spine stability (DA020582, Opioid Receptors in Excitatory Synapses) and, 2) the role of RGS9-2 and its anchoring protein R7BP on drug addiction (DA021743, Molecular Basis of RGS Protein Function in the Striatum). The Center was also successful during the last funding period in providing opportunities for interactions among investigators and for training pre- and post-doctoral fellows. Despite the limited budget, the Center continued to sponsor seminars and organized a biannual symposium to raise the visibility of drug addiction research at the University of Minnesota. Two Center members, Dr. P.Y. Law and Dr. Li-Na Wei, co-chaired the programming committee of the International Narcotic Research Conference held July 9-14, 2006 in St. Paul, Minnesota. These organized activities of the Center, in addition to the weekly research group meetings that are open to all Center members, have generated sustained interest in drug addiction research and opportunities for interactions. Through such activities, Dr. Liao, an expert on AMPA receptor transport and synaptic plasticity, became interested in drug addiction research. Synergism among the various approaches used by Center investigators has facilitated the research progress of individual investigators. This is best reflected by the $5.3 million of national funding obtained during the last fiscal year by the principle investigators associated with the Center and the 20 manuscripts co-authored by the Center's principle investigators during the last funding period. In addition, 2 Center members are recipients of NIDA K05 senior scientist awards (Dr. H.H. Loh and Dr. P.Y. Law), 2 are recipients of NIDA K02 career development awards (Dr. Li-Na Wei and Dr. Sabita Roy) and 1 is a recipient of a NIDA research merit award (Dr. Stanley Thayer). The Center has been and will continue to be national and international source of reagents for drug addiction research. Individual investigators have provided reagents, plasmid constructs, and genetically-altered mice in the Center, and the Administrative Core has assisted in disseminating these materials to intereted investigators, both nationally and internationally. A list of reagents supplied during the last funding period is provided in the subsequent progress report. We remain committed to our goal of attracting young scientists to drug addiction research. One way in which the Center can accomplish this goal, while operating within our budget, is to rotate principle investigators. In the 2002 competitive renewal of our Center, Dr. P.Y. Law did not head an individual scientific component so that we could recruit Dr. Kevin Wickman to our Center. Dr. Law then expanded his original Center component project and successfully competed for an R01 award to pursue his receptor trafficking studies (DA016674, Neuronal Regulation of Opioid Receptor Trafficking). In the last submission, three of the original members of the Center (Dr. Bianca Conti-Fine, Dr. Robert Hide and Dr. Tim Walseth) were replaced with three young scientists (Dr. Kirill Martemyanov, Dr. Jonathan Marchant and Dr. Van Zeng) who were recruited to the Center via the Seed Grant Program. Given the diversity of the proposed research projects, it is understandable that a cohesive scientific theme across the Center was not apparent. Since we wish to remain true to the original goal of the Center, i.e., to foster young scientists in drug addiction research, we have re-organized the Center in this re-submission to focus on the molecular and cell biology of opiate action and addiction. There is no debate on the severity of the problem of opiate addiction. To address and develop treatments for such a severe problem, research on the molecular and cellular mechanisms of drug addiction, and on neural systems and behavior, must be carried out in conjunction with one another. The molecular and cellular analyses cannot focus simply on one aspect of drug addiction. The process of drug signaling that leads to tolerance, dependence, and addiction exhibited by animals must be investigated. The approach cannot be limited simply to gene transcription, but also must include investigations on the actions of gene products that could modify the drug signaling process and neural transmission. Thus, multi-disciplinary approaches that integrate molecular, biochemical, electrophysiological, neuroimmunological and behavioral studies must be applied to the opiate addiction problem. Such an integrated approach could facilitate the rapid implementation of the basic research data into probable treatment paradigms. With this in mind, our proposed Center has several strong points. One clear strength of the Center is the proven track records of Center participants in applying their basic research observations to probable treatments of opiate addiction. An excellent example is the use of clonidine to suppress opiate withdrawal signs in animals, which has been translated into clinical treatment paradigms. Another example is the discovery, during receptor-structure analyses studies, of an opioid receptor mutation that can be activated by opiate alkaloid antagonists. This receptor mutant has been issued a USA patent for the treatment of chronic pain without the tolerance and addiction associated with opiate analgesics. These clinical applications are products of our projects on the molecular and cell biology of opiate action and addiction. Another strength of the Center is the multidisciplinary nature of the proposed research. Well-established faculty who are committed to solving problems of opiate addiction and action head the scientific components of the Center. They are highly-trained experts in transcriptional regulation, biochemical and molecular aspects of receptor signaling, electrophysiology, neuropharmacology, neuroimmunology, and behavioral studies. They have proven records of collaboration, and have worked together synergistically for over a decade. The unique feature of our Center faculty is that collectively, they can investigate opiate addiction from the molecule to the whole animal. As such, our Center faculty provides ample and diverse training opportunities to foster the development of young scientists in the molecular and cell biology of opiate action and addiction.

我们的中心，药物成瘾分子与细胞生物学基础研究中心（MCBDA， www.MCBDA.ahc.umn.edu），成立于 10 年前，其使命是开发药物治疗方法通过基础研究了解药物作用机制来成瘾。我们有 4 个目标设立该中心：(1) 促进药物成瘾研究的跨学科方法； 2）作为 “活动”中心协调和促进有关毒瘾研究的所有学术和学术活动在明尼苏达大学； 3）作为药物成瘾分子和细胞生物学的国家资源研究; 4）作为明尼苏达大学青年科学家培训中心。到目前为止，我们已经成功地实现了这些目标的许多方面。具有 8 个科学组件和行政核心构成了上一个资助期间中心的结构，并且由于多样性以及相关教师的研究兴趣，该中心已成为一个富有成效的中心对毒瘾研究感兴趣的年轻科学家的培训基地。正如我们在讨论中所总结的通过培训和教育部分的种子资助计划（第 55 页），该中心资助了一些年轻科学家提交的创新研究项目。两位种子基金获得者，廖德志博士（神经科学系）和 Kirill Martemyanov 博士（药理学系）使用了结果在中心的支持下产生，以成功竞争 R01 研究奖，旨在：1）研究阿片类药物对树突棘稳定性的调节（DA020582，兴奋性突触中的阿片类受体），2) RGS9-2 及其锚定蛋白 R7BP 对药物成瘾的作用（DA021743，RGS 蛋白的分子基础）纹状体的功能）。在上一个资助期间，该中心还成功地为人们提供了互动的机会。研究人员以及培训博士前和博士后研究员。尽管预算有限，中心仍继续赞助研讨会并组织一年两次的研讨会，以提高吸毒成瘾研究在吸毒成瘾研究中的知名度明尼苏达大学。两名中心成员，P.Y. 博士罗先生和魏丽娜博士共同主持该节目 2006 年 7 月 9 日至 14 日在明尼苏达州圣保罗举行的国际麻醉品研究会议委员会。除了每周向所有人开放的研究小组会议外，中心还组织了这些活动中心成员对毒瘾研究产生了持续的兴趣，并为他们提供了机会互动。 AMPA受体转运和突触可塑性专家廖博士通过这些活动，对毒瘾研究产生了兴趣。中心研究人员使用的各种方法之间的协同促进了研究进展个别调查员。这最好地反映在去年获得的 530 万美元的国家资金中。与该中心相关的主要研究人员的财政年度以及由该中心共同撰写的 20 份手稿中心在上一个资助期间的主要研究人员。此外，还有 2 名中心成员获得 NIDA K05高级科学家奖（H.H. Loh博士和P.Y. Law博士），2位NIDA K02职业生涯获得者发展奖（Li-Na Wei 博士和 Sabita Roy 博士），1 名获得 NIDA 研究优异奖（斯坦利·塞耶博士）。该中心一直并将继续成为国内和国际毒瘾试剂的来源研究。个别研究人员提供了试剂、质粒构建体和转基因小鼠中心和行政核心协助将这些材料传播给感兴趣的人国内和国际的调查人员。上一个资助期间提供的试剂清单是在随后的进度报告中提供。我们仍然致力于吸引年轻科学家参与毒瘾研究的目标。一种方式是该中心可以在我们的预算范围内实现这一目标，即轮换主要研究人员。在 2002 年我们中心的竞争性更新，P.Y. 博士法律并没有领导一个单独的科学组成部分，因此我们可以招募凯文·威克曼博士到我们的中心。罗博士随后扩大了他原来的中心组成部分项目并成功角逐 R01 奖以开展受体贩运研究（DA016674，阿片受体贩运的神经元调节）。在最后一次提交中，三名原始成员中心（Bianca Conti-Fine 博士、Robert Hide 博士和 Tim Walseth 博士）被三名年轻的被招募到该中心的科学家（Kirill Martemyanov 博士、Jonathan Marchant 博士和 Van Zeng 博士）通过种子资助计划。鉴于拟议研究项目的多样性，可以理解的是整个中心的有凝聚力的科学主题并不明显。因为我们希望忠于最初的目标为了培养毒瘾研究领域的年轻科学家，我们对中心进行了重组重新提交重点关注阿片类药物作用和成瘾的分子和细胞生物学。关于阿片成瘾问题的严重性没有争议。解决并开发治疗方法如此严峻的问题，药物成瘾的分子细胞机制、神经网络研究制度和行为必须相互配合才能进行。分子和细胞分析不能仅仅集中于毒瘾的某一方面。药物信号传递过程导致必须对动物表现出的耐受性、依赖性和成瘾性进行研究。该方法不能仅限于基因转录，但还必须包括对基因产物作用的研究可以改变药物信号传导过程和神经传递。因此，多学科方法必须整合分子、生物化学、电生理学、神经免疫学和行为研究应用于鸦片成瘾问题。这种综合方法可以促进快速实施将基础研究数据转化为可能的治疗范式。考虑到这一点，我们提议的中心几个优点。该中心的一项明显优势是中心参与者在以下领域的良好记录：将他们的基础研究观察应用于阿片成瘾的可能治疗方法。一个很好的例子是使用可乐定抑制动物阿片戒断症状，已转化为临床治疗范式。另一个例子是在受体结构分析研究中发现了一种阿片受体突变可被阿片生物碱拮抗剂激活。该受体突变体已被颁发了一项美国专利，用于治疗慢性疼痛，且不会产生耐受性和成瘾性阿片类镇痛药。这些临床应用是我们的分子和细胞生物学项目的产品阿片类药物的作用和成瘾。该中心的另一个优势是拟议研究的多学科性质。师资力量雄厚致力于解决鸦片成瘾问题并采取行动的人领导了该项目的科学组成部分中心。他们是转录调控、生化和分子方面训练有素的专家受体信号传导、电生理学、神经药理学、神经免疫学和行为研究。他们拥有良好的合作记录，并且已经协同工作了十多年。独特的我们中心教师的特点是，他们可以共同研究阿片成瘾，从分子到药物整个动物。因此，我们中心的教师提供充足且多样化的培训机会，以培养年轻科学家在阿片作用和成瘾的分子和细胞生物学方面的发展。