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.
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.
|Chavkin, Charles; Schattauer, Selena S; Levin, Jamie R (2014) Arrestin-mediated activation of p38 MAPK: molecular mechanisms and behavioral consequences. Handb Exp Pharmacol 219:281-92|
|Ehrich, Jonathan M; Phillips, Paul E M; Chavkin, Charles (2014) Kappa opioid receptor activation potentiates the cocaine-induced increase in evoked dopamine release recorded in vivo in the mouse nucleus accumbens. Neuropsychopharmacology 39:3036-48|
|Williams, John T; Ingram, Susan L; Henderson, Graeme et al. (2013) Regulation of *-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev 65:223-54|
|Chavkin, Charles (2013) Dynorphin--still an extraordinarily potent opioid peptide. Mol Pharmacol 83:729-36|
|Smith, Jeffrey S; Schindler, Abigail G; Martinelli, Emma et al. (2012) Stress-induced activation of the dynorphin/ýý-opioid receptor system in the amygdala potentiates nicotine conditioned place preference. J Neurosci 32:1488-95|
|Hays, Sarah L; McPherson, Ronald J; Juul, Sandra E et al. (2012) Long-term effects of neonatal stress on adult conditioned place preference (CPP) and hippocampal neurogenesis. Behav Brain Res 227:7-11|
|Navarro, V M; Gottsch, M L; Wu, M et al. (2011) Regulation of NKB pathways and their roles in the control of Kiss1 neurons in the arcuate nucleus of the male mouse. Endocrinology 152:4265-75|
|Bruchas, Michael R; Schindler, Abigail G; Shankar, Haripriya et al. (2011) Selective p38ýý MAPK deletion in serotonergic neurons produces stress resilience in models of depression and addiction. Neuron 71:498-511|
|Melief, Erica J; Miyatake, Mayumi; Bruchas, Michael R et al. (2010) Ligand-directed c-Jun N-terminal kinase activation disrupts opioid receptor signaling. Proc Natl Acad Sci U S A 107:11608-13|
|Bruchas, Michael R; Chavkin, Charles (2010) Kinase cascades and ligand-directed signaling at the kappa opioid receptor. Psychopharmacology (Berl) 210:137-47|
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