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    Molecular Basis for Kappa-Opioid Regulation of Chemokine Receptor Function

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    Genre
    Thesis/Dissertation
    Date
    2009
    Author
    Finley, Matthew James
    Advisor
    Rogers, Thomas J., 1950-
    Committee member
    Hoffman, Barbara (Biochemist)
    Tsygankov, Alexander Y.
    Liebermann, Dan A., 1949-
    Ganea, Doina
    Department
    Molecular Biology and Genetics
    Subject
    Biology, Molecular
    Biology, Genetics
    Biology, Neuroscience
    Chemokine
    Expression
    Interferon Regulatory Factor
    Opioid, Regulation
    Stat3
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/1217
    
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    DOI
    http://dx.doi.org/10.34944/dspace/1199
    Abstract
    Opioid receptor-mediated regulation of chemokine receptors is vital for the host immune response, development, and neurological function. Previous studies have demonstrated that the kappa opioid receptor (KOR) activation results in decreased infectivity of human immunodeficiency virus 1 (HIV-1) in human peripheral blood mononuclear cells (PBMCs). We have found this effect is due to down-regulation of the major HIV-1 co-receptors, CCR5 and CXCR4. Using molecular techniques, CCR5 and CXCR4 mRNA levels drop dramatically following KOR activation. To dissect the mechanism involved, we used transcription factor binding arrays and compared control cell extracts to KOR activated cell extracts. We determined that the interferon regulatory factors (IRFs) and signal transducers and activators of transcription (STATs) could be involved in the KOR-mediated repression of CCR5 and CXCR4 transcription and protein expression. Using chemical inhibitors and small interfering RNA (siRNA) molecules, we determined that JAK2, STAT3, and IRF2 are critical members of this signal transduction pathway. The understanding of these particular mechanisms should prove to be beneficial for the development of potential pharmacological agents targeted at HIV-1 binding and infection since virus infection requires expression of the co-receptors CXCR4 and CCR5. Understanding the molecular basis for KOR-induced inhibition of co-receptor expression may provide a basis for the development of KOR agonist-based therapeutics to treat individuals infected with HIV.
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