Opioid receptors, at both mRNA and protein levels, are expressed in a temporally and spatially specific manner, suggesting a specific control for their gene expression. It was first hypothesized that the control of the cell (tissue) type- and developmental stage-specificity of the mu opioid receptor (MOR) and the opioid receptor (DOR) is mediated by specific cis-acting DNA sequences of the gene regulatory regions, which interact with various specific regulatory protein (trans-acting) factors. Our previous proposal attempted to examine this hypothesis by first identifying (dissecting) the basic DNA elements responsible for their promoter activities and potential trans-acting factors interacting with these DNA elements. With these basic regulatory elements dissected and identified, it is further hypothesized that manifestation of these regulatory sequences and protein factors may even utilizes a higher order control which involves changes in chromatin structure of the gene pr moter of MOR and DOR. There are three specific aims in this renewal proposal: first, to continue our ungoing studies focused on detailed identification of more components (both cis- and trans-acting factors) for the MOR and the DOR gene regulation, and second to take one step further for the understanding of how these regulatory components interact with each other or with chromatin modification and nucleosome organization of MOR and DOR gene regulatory region, in order to address the physiological relevance of the regulatory components identified from Aim 1.
The third aim will extend these in vitro studies into animals by using transgenic mouse models. Therefore, studies proposed in this renewal grant will utilize a combination of tissue culture systems where MOR and DOR genes are known to be active, such as NS2OY (for DOR) and P19 (for MOR) cells, and transgenic mouse systems where whole animal opioid pharmacology can be examined. It is our ultimate goal to understand the underlying mechanisms for controlling MOR and DOR gene expression, and how these regulatory pathways may interact with exogenous or environmental factors, such as hormones and drugs, to achieve a homeostatic control for MOR and DOR expression in the context of animal physiology.
|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|
|Song, Kyu Young; Choi, Hack Sun; Law, Ping-Yee et al. (2017) Post-Transcriptional Regulation of the Human Mu-Opioid Receptor (MOR) by Morphine-Induced RNA Binding Proteins hnRNP K and PCBP1. J Cell Physiol 232:576-584|
|Wagley, Yadav; Law, Ping-Yee; Wei, Li-Na et al. (2017) Epigenetic Activation of ?-Opioid Receptor Gene via Increased Expression and Function of Mitogen- and Stress-Activated Protein Kinase 1. Mol Pharmacol 91:357-372|
|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|
|Wei, Li-Na; Dmintrovsky, Ethan (2015) Retinoids are back. FASEB J 29:1131-5|
|Macias Konstantopoulos, Wendy L; Dreifuss, Jessica A; McDermott, Katherine A et al. (2014) Identifying patients with problematic drug use in the emergency department: results of a multisite study. Ann Emerg Med 64:516-25|
|Feng, X; Wu, C-Y; Burton, F H et al. (2014) ?-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia. Cell Death Differ 21:397-406|
|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|
|Song, Kyu Young; Choi, Hack Sun; Law, Ping-Yee et al. (2013) Vimentin interacts with the 5'-untranslated region of mouse mu opioid receptor (MOR) and is required for post-transcriptional regulation. RNA Biol 10:256-66|
|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|
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