This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.In the human, the mu-opioid receptor gene contains numerous single nucleotide polymorphisms (SNPs). Among these, an emerging relevance for N40D (or A118G in the DNA) stems from its association with clinical responses to opioidergics, alcohol and opiate sensitivity and dependence, methamphetamine psychosis, aberrant hypothalamic-pituitary-adrenal (HPA) axis function and epilepsy. We discovered a novel P26R SNP in the rhesus monkey mu-opioid receptor that both functionally and phenotypically parallels human N40D. Both human and rhesus monkey alleles have 3.5-fold greater sensitivity to beta-endorphin, and associate with altered hypothalamic-pituitary-adrenal (HPA) axis function. We are identifying SNPs occurring within the coding region and comparing their functional consequences to human SNPs in vitro. We include a focus on mu-opioid receptor expression in immune cells and its documented interaction with CCR5, the major co-receptor for Human and Simian Immunodeficiency Virus (HIV/SIV) entry into cells. As mu-opioid receptor agonists affect CCR5 signaling, modulate CCR5 gene expression and regulate SIV/HIV infectivity, we are exploring an unknown area: do SNPs in the mu-opioid receptor contribute as a host factor in AIDS? Accordingly, we are identifying allelic variants of the rhesus monkey mu-opioid receptor that affect protein structure, and developing genotyping assays to screen for the common alleles. We are also exploring whether mu-opioid receptor genotype influences how endogenous opioid peptides, common opiates and clinically relevant opioidergic drugs may regulate CCR5 and thereby contribute as a relevant host factor in AIDS infection and progression.
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