Building to Illuminate Mechanism of Action and Therapeutic Targets
In 2013, a study led by researchers from the University of North Carolina School of Medicine reported an association between variants in the gene FKBP5 and chronic pain following trauma such as motor vehicle accident or sexual assault. Specifically, they reported, people who possess a variant or minor/risk allele on chromosome 6 are susceptible to greater pain following such events than those without the variant. New work completed by same research team now confirms this association in a study of over 1,500 subjects including people of both European American and African American descent. Lead author Sarah Linnstaedt, PhD, assistant professor of anesthesiology and an investigator in the Institute for Trauma Recovery, commented, “In our current study, we showed that the reason this variant affects chronic pain outcomes is because it alters the ability of FKBP5 to be regulated by a microRNA called miR-320a.” She added, “In individuals with the minor/risk allele, the microRNA does not bind well to FKBP5…thus causing FKBP5 to be over-expressed. High levels of FKBP5 can be detrimental because it alters natural feedback mechanisms that control circulating cortisol (stress hormone) levels.”
MicroRNAs are important in the regulation of gene expression, by degrading the translation of messenger RNA. Cortisol has been demonstrated to directly sensitize peripheral nerves, and subjects with the risk allele have higher levels of the hormone. This places them at risk for experiencing more intense pain following traumatic events than people without the genetic variant. Dr. Linnstaedt suggested that the findings could illuminate new therapeutic targets, observing “I think it suggests we could use small molecules or inhibitor RNAs to decrease expression or inhibit activity of FKBP5, or we could use microRNA mimics to increase expression of the microRNA, miR-320a. I could also imagine a gene editing approach that specifically changes the risk allele in FKBP5 to a protective allele.” The findings were reported in the Journal of Neuroscience.
Read about the study.
The journal abstract may be read here.
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