Controlling FKBP51 for the treatment of PTSD

James A. Haley Va Medical Center, Tampa FL

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Abstract

Though physical wounds have been reduced in recent military conflicts, many Soldiers return home with psychological wounds that manifest as post-traumatic stress disorder (PTSD), depression, and other neuropsychiatric disorders. Some Veterans may be predisposed to these disorders due to the presence of the common rs1360780 single nucleotide polymorphism (SNP) in the FK506-binding protein 5 (FKBP5) gene, which occurs in about 50% of individuals. This SNP is associated with higher expression of FKBP51, the protein encoded by the FKBP5 gene. Data suggest increased FKBP5 expression in the dorsal lateral prefrontal cortex (dlPFC) may be a driver of PTSD and increased FKBP5 levels are reported in the frontal cortex of PTSD patients. Excess FKBP51 dysregulates the hypothalamic-pituitary-adrenal (HPA) axis, the central stress response system. Together, this supports FKBP51 as a potential target for the development of therapeutics to treat PTSD and other neuropsychiatric disorders. The overall goal of this proposal is to develop novel therapeutic strategies to deplete FKBP51, using antisense oligonucleotides, and to validate FKBP51 as a target for regulating resilience in PTSD using mouse models that lack or overexpress FKBP51 exposed to PTSD-like stress. Trauma-induced neuropsychiatric phenotypes and molecular changes will be measured in these studies.