Background: Progress in the molecular biomarkers development in post-traumatic stress disorder (PTSD) has been hampered by an inability to directly access live brain cells for molecular analysis and for comparisons with blood. Additionally, there are no in vitro platforms for identification or testing of potential therapeutic compounds in PTSD.

Objective/Hypothesis: We will use a new method to induce neuronal cells (iNeurons) from skin cells in combat Veterans with and without PTSD and assess RNA expression in these cells and in peripheral blood mononuclear cells (PBMCs) from the same Veterans. The overarching hypothesis is that we can identify PTSD molecular pathways in both iNeurons and PBMCs that would (a) be impacted by glucocorticoids and (b) overlap with comparable pathways detected in our blood biomarkers human studies and in blood and brain of animals with PTSD-like phenotypes.

Specific Aims: (1) To induce and culture iNeurons and in parallel to culture PBMCs from blood of combat Veterans with and without PTSD. (2) To identify PTSD associated differential gene expression in iNeurons and PBMCs. (3) To measure PTSD-specific transcriptomic response to glucocorticoid stimulation in iNeurons and PBMCs. (4) To develop PTSD causal gene co-expression network that integrates iNeuron and PBMC gene expression data with previously obtain human/animal data.

Study Design: We will recruit combat Veterans with and without PTSD and obtain their blood and skin cells. The skin cells will be reprogrammed into stem cells and then into iNeurons. Both live blood cells and iNeurons will be stimulated with vehicle or glucocorticoids. RNA sequencing will be performed, and computational analyses will determine (i) neuron/blood cell relationships, (ii) the effect of glucocorticoids on gene expression in these cells, and (iii) unique signatures associated with PTSD.

Relevance: The demonstration of a relationship between blood and brain cell molecular networks in combat Veterans with and without PTSD provides critical proof of concept for using blood biomarkers for diagnostic purposes and can advance treatment objectives. We will also integrate the data obtained from this study with additional data to develop a gene network with predictive validity for PTSD in which novel therapeutics could be predicted, and in the future tested.