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 drugaddiction by understanding the mechanisms of drug actions, via basic research. We had 4 objectives when weestablished 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 researchat University of Minnesota; 3) to serve as a national resource for molecular and cell biology of drug addictionresearch; and 4) to serve as training Center for young scientists at the University of Minnesota. Thus far, wehave been successful in accomplishing many aspects of these objectives. With 8 scientific components and anAdministrative Core constituting the structure of Center during the last funding period, and due to the diversityand breath in the research interests of the faculty involved, the Center has established itself as a productivetraining ground for young scientists interested in drug addiction research. As summarized in our discussion ofthe Seed Grant Program in the Training and Education section (page 55), the Center has funded someinnovative 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 resultsgenerated with Center support to successfully compete for R01 research awards aimed at: 1) the study ofopioid regulation of dendritic spine stability (DA020582, Opioid Receptors in Excitatory Synapses) and, 2) therole of RGS9-2 and its anchoring protein R7BP on drug addiction (DA021743, Molecular Basis of RGS ProteinFunction in the Striatum).The Center was also successful during the last funding period in providing opportunities for interactions amonginvestigators and for training pre- and post-doctoral fellows. Despite the limited budget, the Center continued tosponsor seminars and organized a biannual symposium to raise the visibility of drug addiction research at theUniversity of Minnesota. Two Center members, Dr. P.Y. Law and Dr. Li-Na Wei, co-chaired the programmingcommittee 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 allCenter members, have generated sustained interest in drug addiction research and opportunities forinteractions. 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 progressof individual investigators. This is best reflected by the $5.3 million of national funding obtained during the lastfiscal year by the principle investigators associated with the Center and the 20 manuscripts co-authored by theCenter's principle investigators during the last funding period. In addition, 2 Center members are recipients ofNIDA K05 senior scientist awards (Dr. H.H. Loh and Dr. P.Y. Law), 2 are recipients of NIDA K02 careerdevelopment 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 addictionresearch. Individual investigators have provided reagents, plasmid constructs, and genetically-altered mice inthe Center, and the Administrative Core has assisted in disseminating these materials to interetedinvestigators, both nationally and internationally. A list of reagents supplied during the last funding period isprovided in the subsequent progress report.We remain committed to our goal of attracting young scientists to drug addiction research. One way in whichthe Center can accomplish this goal, while operating within our budget, is to rotate principle investigators. Inthe 2002 competitive renewal of our Center, Dr. P.Y. Law did not head an individual scientific component sothat we could recruit Dr. Kevin Wickman to our Center. Dr. Law then expanded his original Center componentproject 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 ofthe Center (Dr. Bianca Conti-Fine, Dr. Robert Hide and Dr. Tim Walseth) were replaced with three youngscientists (Dr. Kirill Martemyanov, Dr. Jonathan Marchant and Dr. Van Zeng) who were recruited to the Centervia the Seed Grant Program. Given the diversity of the proposed research projects, it is understandable that acohesive scientific theme across the Center was not apparent. Since we wish to remain true to the original goalof the Center, i.e., to foster young scientists in drug addiction research, we have re-organized the Center in thisre-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 forsuch a severe problem, research on the molecular and cellular mechanisms of drug addiction, and on neuralsystems and behavior, must be carried out in conjunction with one another. The molecular and cellularanalyses cannot focus simply on one aspect of drug addiction. The process of drug signaling that leads totolerance, dependence, and addiction exhibited by animals must be investigated. The approach cannot belimited simply to gene transcription, but also must include investigations on the actions of gene products thatcould modify the drug signaling process and neural transmission. Thus, multi-disciplinary approaches thatintegrate molecular, biochemical, electrophysiological, neuroimmunological and behavioral studies must beapplied to the opiate addiction problem. Such an integrated approach could facilitate the rapid implementationof the basic research data into probable treatment paradigms. With this in mind, our proposed Center hasseveral strong points. One clear strength of the Center is the proven track records of Center participants inapplying their basic research observations to probable treatments of opiate addiction. An excellent example isthe use of clonidine to suppress opiate withdrawal signs in animals, which has been translated into clinicaltreatment paradigms. Another example is the discovery, during receptor-structure analyses studies, of anopioid receptor mutation that can be activated by opiate alkaloid antagonists. This receptor mutant has beenissued a USA patent for the treatment of chronic pain without the tolerance and addiction associated withopiate analgesics. These clinical applications are products of our projects on the molecular and cell biology ofopiate action and addiction.Another strength of the Center is the multidisciplinary nature of the proposed research. Well-established facultywho are committed to solving problems of opiate addiction and action head the scientific components of theCenter. They are highly-trained experts in transcriptional regulation, biochemical and molecular aspects ofreceptor signaling, electrophysiology, neuropharmacology, neuroimmunology, and behavioral studies. Theyhave proven records of collaboration, and have worked together synergistically for over a decade. The uniquefeature of our Center faculty is that collectively, they can investigate opiate addiction from the molecule to thewhole animal. As such, our Center faculty provides ample and diverse training opportunities to foster thedevelopment 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 #
2P50DA011806-11A1
Application #
7612851
Study Section
Special Emphasis Panel (ZDA1-RXL-E (05))
Project Start
2008-09-30
Project End
2013-06-30
Budget Start
2008-09-30
Budget End
2009-06-30
Support Year
11
Fiscal Year
2008
Total Cost
$264,855
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
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, 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
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
Wang, Yan; Ge, Yan-Hui; Wang, Yan-Xia et al. (2015) Modulation of mTOR Activity by ?-Opioid Receptor is Dependent upon the Association of Receptor and FK506-Binding Protein 12. CNS Neurosci Ther 21:591-8
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

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