# Silvio O. Conte Center for Stress Peptide Advanced Research, Education, & Dissemination (SPARED) at McLean Hospital

> **NIH NIH P50** · MCLEAN HOSPITAL · 2021 · $102,615

## Abstract

PROJECT SUMMARY/ABSTRACT
 Post-traumatic stress disorder (PTSD) is a chronic, debilitating, mental disorder that occurs in
susceptible individuals after traumatic stress exposure, with a prevalence of ~8%. While pathway driven
approaches and molecular profiling have implicated multiple biological systems in PTSD, there are no
established biomarkers or effective treatments due to the incomplete understanding of the disorder’s complex
mechanisms. This partial understanding is significantly restricted by our reliance on studying PTSD with human
blood and post mortem brain samples, due to limited access to living human PTSD neural tissue. Without a
significant breakthrough, PTSD will continue to be a severe public health and socio-economic burden.
 The hypothalamic-pituitary-adrenal (HPA) axis has been much studied in PTSD since it is the central
coordinator of the neuroendocrine response to traumatic stress. HPA-axis imbalance in PTSD involves low
glucocorticoid (GC) signaling due to low circulating GC levels, and epigenetic dysregulation of certain GC
related genes has been shown to be pathogenic for PTSD. Various studies have utilized the synthetic GC,
dexamethasone (DEX), to model the epigenetic and transcriptional effects of PTSD associated stress with in
vitro and in vivo models. Yet, the mechanisms for how GC dysregulation develops into PTSD are not fully
uncovered, and accurate GC-based biomarkers and treatments are lacking.
 Elucidating the pathogenesis of PTSD has been challenging, but other psychiatric disorders’ molecular
etiologies have been successfully illuminated with induced pluripotent stem cell (iPSC) modeling, possibly due
to the approaches’ capacity to interrogate diseases while controlling for genetics and external stimuli. To date,
human neurons containing PTSD pathology (genetics, epigenetics, and transcriptomics) have never been
interrogated in vitro. A recent advancement beyond iPSC modeling, transdifferentiation of human blood
lymphocytes into neurons via direct reprogramming, opens the door for PTSD to be studied holistically. As an
acquired disease, evidence is growing about the role epigenetic marks acquired from life stress plays in PTSD
pathogenesis, and there is currently no in vitro modality for capturing human PTSD epigenetics in neural
tissue, as typical induced pluripotent stem cell reprogramming resets the epigenetic landscape. Excitingly,
evidence suggests directly reprogrammed neurons (iNs) can maintain their original cell’s epigenetic signatures.
 The objective for this award is to begin to model the genetics and epigenetics of PTSD in human
lymphocytes differentiated to iNs in basal and GC-exposed conditions and determine molecular differences
across groups. We postulate that identifying methylation and gene expression changes due to GC activity that
are shared across lymphocytes and iNs in PTSD individuals will allow for better discrimination and detection of
the key pathways driving PTSD pathogenesis.

## Key facts

- **NIH application ID:** 10376397
- **Project number:** 3P50MH115874-03S1
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** William A. Carlezon
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $102,615
- **Award type:** 3
- **Project period:** 2019-04-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376397

## Citation

> US National Institutes of Health, RePORTER application 10376397, Silvio O. Conte Center for Stress Peptide Advanced Research, Education, & Dissemination (SPARED) at McLean Hospital (3P50MH115874-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10376397. Licensed CC0.

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