Matthew Girgenti, PhD

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.