It has been well documented that the mu, opioid, and kappa opioid receptors are differentially localized in distinct areas of the nervous system, and they can be detected beginning in early developmental stage, as early as mid-gestation stages in prenatal development. It is also known that the opioid receptors respond to environmental, physiological or pharmacological stimuli, which is manifested by alteration in neuronal and behavioral responses. Since the recent successful cloning of all the major opioid receptor cDNAs and the genes encoding the three receptors, it becomes clear that these genes evolved are from a common ancestral gene, but unique regulatory mechanisms are adopted for these gene expression as they evolve. Among the three genes, the mouse KOR gene is most interesting in its 5' untranslated region where two alternative promoters are used and differential splicing occurs in intron 1. Two questions are asked: 1. What are the biological functions of the duo-promoters of mouse KOR gene, and 2. How are they regulated? This proposal will focus on specific regulatory mechanisms underlying specific KOR gene expression in three aims.
The first aim will address the specific activity of the dual promoters, the second aim will address the regulatory activity (cell-type and developmental specificity) of these promoters and the upstream region, including a potential silencer element, and the third aim will use transgenic mouse models to confirm genetic information generated from the first two aims and to examine novel regulatory mechanisms for KOR expression in the whole animals.
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