This application is for a renewal of a NIDA sponsored K02 (DA13926) Independent Scientist Award. The current K02 award (2002-2007) allowed the PI to develop her independent research career that focuses on genetic programming for the expression of drug receptors, in particular, the opioid receptors. It is known that the amounts of opioid receptors are crucial for the analgesic effects of opioid compounds. The control is through genetic programming that instructs the cells to express these genes properly and specifically (transcriptional control) and to produce these proteins from mRNAs (post-transcriptionally) according to the needs. In the previous studies, the major task was to dissect the basic elements responsible for transcriptional and post-transcriptional regulation of opioid receptor genes, that include determining DMA sequences and protein factors required for transcriptional control, identification of post-transcriptional events that modulate the rate, the place and the time of opioid receptor protein production in neurons, and dissecting fundamentally important mechanisms in their regulation. Over the period of 2002-2005 supported by this K02, the Pi's works were published in 35 papers. The renewal proposal will continue systemic investigation into the mechanistic basis of these biological processes and the integration in the animals for understanding the homeostatic control of opioid receptor expression. Thus, the overall direction of the research project remains the same.
Specific aims are: 1) to extend studies of transcriptional regulation of KOR gene by focusing on how transcription factors interact with chromatin of the KOR gene, leading to chromatin remodeling of the promoter regions;2) to identify post-transcriptional events that regulate KOR protein production in neurons by focusing on the control of mRNA transport and local translation in neurons regulated by the 5'- and the 3'-untranslated regions;and 3) to produce transgenic mouse models to answer whether and how these regulatory events affect the manifestation of pharmacological effects and problems of opioids, such as addiction and tolerance. These studies are clinically important for the identification of crucial steps in genetic programming of opioid receptor expression that may shed light on potential targets of interventions for drug abuse problems, and are fundamentally applicable for the understanding of critical biological processes required for neuronal compartment-specific expression of proteins that are of significant pharmacological and neurological consequences. This award is also essential for the Pi's continual career development as an independent scientist in the field of drug abuse research.
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