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Matthew J Girgenti, PhD

Assistant Professor of Psychiatry

Contact Information

Matthew J Girgenti, PhD

Mailing Address

  • 34 Park Street

    CMHC

    New Haven, CT 06508

    United States

Research Summary

Research in our lab is directed at determining the molecular pathologies underlying stress disorders such post-traumatic stress disorder (PTSD), major depressive disorder (MDD), and suicidal behavior. We identify therapeutic and biomarker targets relevant to those disorders by utilizing human brain derived data from frozen postmortem tissue. We conduct research focused on the connection between stress and brain functions. My lab employs functional genomics to dissect transcriptomic and cell-type-specific regulatory elements and risk loci underlying the genetics of stress-related mental disorders and engages in translational research using animal models and donor-derived human induced pluripotent stem cells (hiPSCs) to validate causal genes and variants. In addition, my lab employs “big data” approaches to investigate single cell-type molecular dysregulations of complex neuropsychiatric traits to gain a deeper understanding of the individual differences in the expression of symptoms. Together, this work is contributing importantly to the evolving understanding of PTSD and depression and their treatment at the molecular, cellular, and behavioral levels.

Extensive Research Description

While recent large-scale genetic association studies have identified numerous risk loci for PTSD and MDD, the mechanisms through which they contribute to disease remain largely unknown. By applying single cell molecular approaches to the affected tissue (in this case, the human brain), we can uncover novel cellular subpopulations that are associated with these disorders. In parallel, cell type-specific molecular studies allow us to characterize the effect of genetic variation on the complex mechanisms that regulate gene expression in those cells relevant to disease. The goal of our research is to identify causal genes and therapeutic targets relevant to stress-related disorders utilizing human brain derived datasets from frozen postmortem tissue across multiple brain regions and diagnostic groups and couple those with hIPSCs and animal models to understand the neurobiological mechanisms involved.

Current projects include:

  • Cell type-specific genomic atlas of stress disorders- we are currently profiling 2 molecular modalities (transcriptome and epigenome) in 10 human postmortem brain regions across 3 diagnostic cohorts PTSD, MDD, and normal control donors.
  • Functional characterization of PTSD risk variants- here we are expanding upon the rich transcriptomic data generated from our PTSD and MDD postmortem brain tissue by incorporating genome-scale DNA methylation (DNAm) data, alternative splicing, and non-coding RNAs with genetic data to better determine how genetic risk for PTSD and MDD manifests in the human brain.
  • iPSC Functional Validation of PTSD causal genes- we are applying hiPSC-based approaches to manipulate the genotype and/or expression levels of a putative causal risk genes identified in large GWAS and postmortem datasets.
  • Animal models of traumatic and chronic stress- we are validating our molecular findings using a broad array of mouse models and techniques (viral vectors and genetic mutants) in females and males to characterize the behavioral and molecular mechanisms of stress-related disorders.
  • Molecular pathology of suicide- We are identifying cell types, networks, and genes with causal roles in suicide by comparing transcriptomic signatures of PTSD and MDD subjects with or without death by suicide.

Coauthors

Research Interests

Anxiety Disorders; Behavior and Behavior Mechanisms; Genetics; Neurobiology; Neurosciences; Stress Disorders, Post-Traumatic; Stress, Psychological; Suicide; Genomics; Proteomics; Transcriptome

Selected Publications