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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA011806-12
Application #
7884433
Study Section
Special Emphasis Panel (ZDA1)
Project Start
Project End
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
12
Fiscal Year
2009
Total Cost
$548,241
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Hwang, Cheol Kyu; Wagley, Yadav; Law, Ping-Yee et al. (2017) Phosphorylation of poly(rC) binding protein 1 (PCBP1) contributes to stabilization of mu opioid receptor (MOR) mRNA via interaction with AU-rich element RNA-binding protein 1 (AUF1) and poly A binding protein (PABP). Gene 598:113-130
Kibaly, Cherkaouia; Lin, Hong-Yiou; Loh, Horace H et al. (2017) Spinal or supraspinal phosphorylation deficiency at the MOR C-terminus does not affect morphine tolerance in vivo. Pharmacol Res 119:153-168
Banerjee, S; Sindberg, G; Wang, F et al. (2016) Opioid-induced gut microbial disruption and bile dysregulation leads to gut barrier compromise and sustained systemic inflammation. Mucosal Immunol 9:1418-1428
Kibaly, Cherkaouia; Kam, Angel Y F; Loh, Horace H et al. (2016) Naltrexone Facilitates Learning and Delays Extinction by Increasing AMPA Receptor Phosphorylation and Membrane Insertion. Biol Psychiatry 79:906-16
Meng, Jingjing; Roy, Sabita (2016) Study of Epithelium Barrier Functions by Real-time TER Measurement. Bio Protoc 6:
Banerjee, Santanu; Ninkovic, Jana; Meng, Jingjing et al. (2015) Morphine compromises bronchial epithelial TLR2/IL17R signaling crosstalk, necessary for lung IL17 homeostasis. Sci Rep 5:11384
Wang, Yan; Wang, Yan-Xia; Liu, Ting et al. (2015) ?-Opioid receptor attenuates A? oligomers-induced neurotoxicity through mTOR signaling. CNS Neurosci Ther 21:8-14
Meng, Jingjing; Banerjee, Santanu; Li, Dan et al. (2015) Opioid Exacerbation of Gram-positive sepsis, induced by Gut Microbial Modulation, is Rescued by IL-17A Neutralization. Sci Rep 5:10918
Kotecki, Lydia; Hearing, Matthew; McCall, Nora M et al. (2015) GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner. J Neurosci 35:7131-42
Hwang, Cheol Kyu; Wagley, Yadav; Law, Ping-Yee et al. (2015) Analysis of epigenetic mechanisms regulating opioid receptor gene transcription. Methods Mol Biol 1230:39-51

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