The purpose of this K02 application is to seek salary support for scientific career development of the PI at the Dept. Pharmacology of Univ. Minnesota Medical School. The PI was trained in molecular biology and genetics with special focus on interaction of hormone nuclear receptors and transcription factors. She has initiated a research project (DA-11190) aimed to study regulatory mechanisms for kappa opioid receptor (KOR) gene regulation. In order to develop her sceintific career along the line of drug abuse research and perform several experiments described in this project, she plans to devote more time into her research and receive further training in developmental neurobiology and opioid pharmacology. The project proposed is based upon the currently funded R01 to examine several important regulatory mechanisms underlying KOR gene expression.
Three aims are proposed to address two fundamental problems in KOR gene regulation: transcription and post-transcriptional mechanisms for controlling KOR expression.
Three aims are: 1)To Study Transcriptional Regulation of Mouse KOR Gene, 2) To Study Post-transcriptional Regulation of Mouse KOR Expression and 3) Transgenic Mouse Models to Study KOR Ontogeny and Regulation.
The first aim will address transcriptional control by focusing on a retinoic acid (RA)-regulated silencer element located in intron 1 of the gene, and the positive mechanisms regulating promoters 1 and 2. The mechanisms underlying histone deacetylation on KOR promoters as a result of retinoid depletion will be addressed. Protein factors responsible for the activation of KOR gene in KOR neurons will be identified. An embryonic cell line P19 that is capable of differentiation into various cell lineages including KOR neurons and expresses KOR in an RA-regulated manner will be used. In the second aim, mRNA transport and protein translation efficiency will be examined in relation to the cell- and tissue type-specificity of KOR expression. The information gathered from aims 1 and 2 deals with KOR regulation in vitro.
The third aim i s to confirm and correct the information generated from in vitro models by using transgenic mouse models. These genetic studies will answer whether and how pharmacological problems, such as opioid addiction and tolerance, may be related to the endocrine system such as retinoid status and the homeostatic control of opioid receptor gene activity. The granting of this award will enable the PI to devote more time into her research projects and take leave of absence to receive training. This award is essential for the PI?s career development as a more productive and contributing scientist in the field of drug abuse research.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DA013926-02
Application #
6621101
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Rutter, Joni
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$103,092
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
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
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
Wagley, Yadav; Hwang, Cheol Kyu; Lin, Hong-Yiou et al. (2013) Inhibition of c-Jun NH2-terminal kinase stimulates mu opioid receptor expression via p38 MAPK-mediated nuclear NF-?B activation in neuronal and non-neuronal cells. Biochim Biophys Acta 1833:1476-88
Wu, Qifang; Hwang, Cheol Kyu; Zheng, Hui et al. (2013) MicroRNA 339 down-regulates ?-opioid receptor at the post-transcriptional level in response to opioid treatment. FASEB J 27:522-35
Persaud, Shawna D; Lin, Yi-Wei; Wu, Cheng-Ying et al. (2013) Cellular retinoic acid binding protein I mediates rapid non-canonical activation of ERK1/2 by all-trans retinoic acid. Cell Signal 25:19-25
Ho, Ping-Chih; Tsui, Yao-Chen; Feng, Xudong et al. (2012) NF-?B-mediated degradation of the coactivator RIP140 regulates inflammatory responses and contributes to endotoxin tolerance. Nat Immunol 13:379-86
Kang, Duk-Hee; Song, Kyu Young; Choi, Hack Sun et al. (2012) Novel dual-binding function of a poly (C)-binding protein 3, transcriptional factor which binds the double-strand and single-stranded DNA sequence. Gene 501:33-8
Ho, Ping-Chih; Tsui, Yao-Chen; Lin, Yi-Wei et al. (2012) Endothelin-1 promotes cytoplasmic accumulation of RIP140 through a ET(A)-PLCýý-PKCýý pathway. Mol Cell Endocrinol 351:176-83
Song, Kyu Young; Choi, Hack Sun; Law, Ping-Yee et al. (2012) Post-transcriptional regulation of mu-opioid receptor: role of the RNA-binding proteins heterogeneous nuclear ribonucleoprotein H1 and F. Cell Mol Life Sci 69:599-610
Wei, Li-Na (2012) Chromatin remodeling and epigenetic regulation of the CrabpI gene in adipocyte differentiation. Biochim Biophys Acta 1821:206-12

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