Targeted Discovery and Characterization of Opioid Use Disorder (OUD) Causal Genes Through Proteomic Analysis of Human Brain Regions

Vena Martinez, Department of Psychiatry, Yale University

Opioid overdoses continue to increase, despite newly available treatments and enhanced legal regulations. New therapeutic targets are urgently needed. Opioid use disorder (OUD) is twice as likely to develop in PTSD patients, and OUD patients with PTSD have a greater risk of increased OUD severity. This suggests predisposing risk factors exist for the development and severity of OUD in patients with PTSD and perhaps other psychiatric disorders. The amygdala is a significant brain region of convergence between OUD and PTSD, regulating positive and negative emotional states for both conditions. Additionally, altered amygdala structure and volume have been reported in both conditions. We previously conducted transcriptomic profiles in human postmortem amygdala and identified differentially expressed transcripts for both OUD and PTSD. In collaboration with Yale/NIDA Neuroproteomic Center’s Discovery Proteomics Core, we propose a pilot study to identify differentially expressed proteins and causal genes in OUD+, PTSD+, OUD+PTSD, and normal control (NC) postmortem amygdala. In Aim 1, we will generate comprehensive proteomic profiles for each condition. We will use our uniquely developed, state-of-the-art bioinformatic pipeline to integrate transcriptomic and proteomic profiles, and identify sex-specific differences. In addition, we will conduct proteomic co-expression analysis to identify cell type-specific differences in OUD. We will extend our studies to identify single cell type proteomic changes in Aim 2 by using laser capture microdissection on frozen sections of OUD and PTSD postmortem tissue. We will then conduct proteomic profiling and pathway analysis to identify dysregulated expression of neuronal and non-neuronal cells. These preliminary findings will identify biological factors that can be mechanistically interrogated in animal studies to potentially advance diagnostics and therapeutics of OUD.