Matthew Girgenti, PhD
Research & Publications
Biography
News
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
- Genetic liability to suicidal thoughts and behaviors and risk of suicide attempt in US military veterans: moderating effects of cumulative trauma burden.Nichter B, Koller D, De Angelis F, Wang J, Girgenti M, Na P, Hill M, Norman S, Krystal J, Gelernter J, Polimanti R, Pietrzak R. Genetic liability to suicidal thoughts and behaviors and risk of suicide attempt in US military veterans: moderating effects of cumulative trauma burden. Psychological Medicine 2022, 1-9. PMID: 36444557, DOI: 10.1017/s0033291722003646.
- Venus: An efficient virus infection detection and fusion site discovery method using single-cell and bulk RNA-seq dataLee CY, Chen Y, Duan Z, Xu M, Girgenti MJ, Xu K, Gerstein M, Zhang J. Venus: An efficient virus infection detection and fusion site discovery method using single-cell and bulk RNA-seq data PLOS Computational Biology 2022, 18: e1010636. PMID: 36301997, PMCID: PMC9642901, DOI: 10.1371/journal.pcbi.1010636.
- Molecular and cellular evolution of the primate dorsolateral prefrontal cortexMa S, Skarica M, Li Q, Xu C, Risgaard RD, Tebbenkamp ATN, Mato-Blanco X, Kovner R, Krsnik Ž, de Martin X, Luria V, Martí-Pérez X, Liang D, Karger A, Schmidt DK, Gomez-Sanchez Z, Qi C, Gobeske KT, Pochareddy S, Debnath A, Hottman CJ, Spurrier J, Teo L, Boghdadi AG, Homman-Ludiye J, Ely JJ, Daadi EW, Mi D, Daadi M, Marín O, Hof PR, Rasin MR, Bourne J, Sherwood CC, Santpere G, Girgenti MJ, Strittmatter SM, Sousa AMM, Sestan N. Molecular and cellular evolution of the primate dorsolateral prefrontal cortex Science 2022, 377: eabo7257. PMID: 36007006, PMCID: PMC9614553, DOI: 10.1126/science.abo7257.
- Translator: A Transfer Learning Approach to Facilitate Single-Cell ATAC-Seq Data Analysis from Reference DatasetXu S, Skarica M, Hwang A, Dai Y, Lee C, Girgenti MJ, Zhang J. Translator: A Transfer Learning Approach to Facilitate Single-Cell ATAC-Seq Data Analysis from Reference Dataset Journal Of Computational Biology 2022, 29: 619-633. PMID: 35584295, PMCID: PMC9464368, DOI: 10.1089/cmb.2021.0596.
- Positive modulation of N-methyl-D-aspartate receptors in the mPFC reduces the spontaneous recovery of fearLee B, Pothula S, Wu M, Kang H, Girgenti MJ, Picciotto MR, DiLeone RJ, Taylor JR, Duman RS. Positive modulation of N-methyl-D-aspartate receptors in the mPFC reduces the spontaneous recovery of fear Molecular Psychiatry 2022, 27: 2580-2589. PMID: 35418600, PMCID: PMC9135632, DOI: 10.1038/s41380-022-01498-7.
- Matthew J. Friedman, M.D., Ph.D. and His Legacy of Leadership in the Field of Post-traumatic Stress DisorderKrystal JH, Southwick SM, Girgenti MJ. Matthew J. Friedman, M.D., Ph.D. and His Legacy of Leadership in the Field of Post-traumatic Stress Disorder Psychiatry 2022, 85: 161-170. PMID: 35588483, DOI: 10.1080/00332747.2022.2068931.
- InsuLock: A Weakly Supervised Learning Approach for Accurate Insulator Prediction, and Variant Impact QuantificationSrinivasan S, Gong Y, Xu S, Hwang A, Xu M, Girgenti M, Zhang J. InsuLock: A Weakly Supervised Learning Approach for Accurate Insulator Prediction, and Variant Impact Quantification Genes 2022, 13: 621. PMID: 35456427, PMCID: PMC9026820, DOI: 10.3390/genes13040621.
- A Role for Histone Deacetylases in the Biology and Treatment of Post-Traumatic Stress Disorder: What Do We Know and Where Do We Go from Here?Bonomi R, Girgenti M, Krystal J, Cosgrove K. A Role for Histone Deacetylases in the Biology and Treatment of Post-Traumatic Stress Disorder: What Do We Know and Where Do We Go from Here? Complex Psychiatry 2022, 8: 13-27. PMCID: PMC9669946, DOI: 10.1159/000524079.
- Transcriptomics of the depressed and PTSD brainZhang J, Kaye AP, Wang J, Girgenti MJ. Transcriptomics of the depressed and PTSD brain Neurobiology Of Stress 2021, 15: 100408. PMID: 34703849, PMCID: PMC8524242, DOI: 10.1016/j.ynstr.2021.100408.
- Gene expression in the dorsolateral and ventromedial prefrontal cortices implicates immune-related gene networks in PTSDLogue MW, Zhou Z, Morrison FG, Wolf EJ, Daskalakis NP, Chatzinakos C, Georgiadis F, Labadorf AT, Girgenti MJ, Young KA, Williamson DE, Zhao X, Grenier JG, Group T, Huber BR, Miller MW. Gene expression in the dorsolateral and ventromedial prefrontal cortices implicates immune-related gene networks in PTSD Neurobiology Of Stress 2021, 15: 100398. PMID: 34646915, PMCID: PMC8498459, DOI: 10.1016/j.ynstr.2021.100398.
- Posttraumatic Stress Disorder Brain Transcriptomics: Convergent Genomic Signatures Across Biological SexWang J, Zhao H, Girgenti MJ. Posttraumatic Stress Disorder Brain Transcriptomics: Convergent Genomic Signatures Across Biological Sex Biological Psychiatry 2021, 91: 6-13. PMID: 33840456, DOI: 10.1016/j.biopsych.2021.02.012.
- Transcriptomic organization of the human brain in post-traumatic stress disorderGirgenti MJ, Wang J, Ji D, Cruz DA, Stein M, Gelernter J, Young K, Huber B, Williamson D, Friedman M, Krystal J, Zhao H, Duman R. Transcriptomic organization of the human brain in post-traumatic stress disorder Nature Neuroscience 2020, 24: 24-33. PMID: 33349712, DOI: 10.1038/s41593-020-00748-7.
- Stress and its impact on the transcriptomeGirgenti MJ, Pothula S, Newton SS. Stress and its impact on the transcriptome Biological Psychiatry 2020, 90: 102-108. PMID: 33637305, PMCID: PMC8213869, DOI: 10.1016/j.biopsych.2020.12.011.
- Cortical Transcriptomic Alterations in Association with Appetitive Neuropeptides and Body Mass Index in Posttraumatic Stress DisorderStone LA, Girgenti MJ, Wang J, Ji D, Zhao H, Krystal JH, Group T, Duman R. Cortical Transcriptomic Alterations in Association with Appetitive Neuropeptides and Body Mass Index in Posttraumatic Stress Disorder The International Journal Of Neuropsychopharmacology 2020, 24: pyaa072-. PMID: 32951025, PMCID: PMC8611677, DOI: 10.1093/ijnp/pyaa072.
- PTSD is associated with neuroimmune suppression: evidence from PET imaging and postmortem transcriptomic studiesBhatt S, Hillmer AT, Girgenti MJ, Rusowicz A, Kapinos M, Nabulsi N, Huang Y, Matuskey D, Angarita GA, Esterlis I, Davis MT, Southwick SM, Friedman MJ, Duman R, Carson R, Krystal J, Pietrzak R, Cosgrove K. PTSD is associated with neuroimmune suppression: evidence from PET imaging and postmortem transcriptomic studies Nature Communications 2020, 11: 2360. PMID: 32398677, PMCID: PMC7217830, DOI: 10.1038/s41467-020-15930-5.
- Transcriptomic Organization of Human Posttraumatic Stress DisorderGirgenti M, Wang J, Ji D, Cruz D, Group T, Program M, Stein M, Gelernter J, Young K, Huber B, Williamson D, Friedman M, Krystal J, Zhao H, Duman R. Transcriptomic Organization of Human Posttraumatic Stress Disorder Biological Psychiatry 2020, 87: s122. DOI: 10.1016/j.biopsych.2020.02.330.
- Neural Transcriptomic Alterations Associated With Neuropeptide Y and Ghrelin in Posttraumatic Stress DisorderStone L, Girgenti M, Krystal J, Duman R, Group T. Neural Transcriptomic Alterations Associated With Neuropeptide Y and Ghrelin in Posttraumatic Stress Disorder Biological Psychiatry 2020, 87: s421-s422. DOI: 10.1016/j.biopsych.2020.02.1075.
- GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actionsGerhard DM, Pothula S, Liu RJ, Wu M, Li XY, Girgenti MJ, Taylor SR, Duman CH, Delpire E, Picciotto M, Wohleb ES, Duman RS. GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions Journal Of Clinical Investigation 2020, 130: 1336-1349. PMID: 31743111, PMCID: PMC7269589, DOI: 10.1172/jci130808.
- Prefrontal cortex interneurons display dynamic sex-specific stress-induced transcriptomesGirgenti MJ, Wohleb ES, Mehta S, Ghosal S, Fogaca MV, Duman RS. Prefrontal cortex interneurons display dynamic sex-specific stress-induced transcriptomes Translational Psychiatry 2019, 9: 292. PMID: 31712551, PMCID: PMC6848179, DOI: 10.1038/s41398-019-0642-z.
- Ketamine rapidly reverses stress-induced impairments in GABAergic transmission in the prefrontal cortex in male rodentsGhosal S, Duman CH, Liu RJ, Wu M, Terwilliger R, Girgenti MJ, Wohleb E, Fogaca MV, Teichman EM, Hare B, Duman RS. Ketamine rapidly reverses stress-induced impairments in GABAergic transmission in the prefrontal cortex in male rodents Neurobiology Of Disease 2019, 134: 104669. PMID: 31707118, DOI: 10.1016/j.nbd.2019.104669.
- Analysis of Bulk Tissue Transcriptome Data Reveals Convergence of Cell Types Altered in Schizophrenia and Bipolar DisorderGirgenti MJ, Duman RS. Analysis of Bulk Tissue Transcriptome Data Reveals Convergence of Cell Types Altered in Schizophrenia and Bipolar Disorder Biological Psychiatry 2018, 84: 772-774. PMID: 30409264, DOI: 10.1016/j.biopsych.2018.09.014.
- Molecular and cellular studies of PTSD: Postmortem transcriptome analysis and novel therapeutic targetsDuman RS, Girgenti MJ. Molecular and cellular studies of PTSD: Postmortem transcriptome analysis and novel therapeutic targets Journal Of Neuroscience Research 2018, 97: 292-299. PMID: 30136735, DOI: 10.1002/jnr.24306.
- Transcriptome Alterations in Posttraumatic Stress DisorderGirgenti MJ, Duman RS. Transcriptome Alterations in Posttraumatic Stress Disorder Biological Psychiatry 2017, 83: 840-848. PMID: 29128043, DOI: 10.1016/j.biopsych.2017.09.023.
- Molecular and Cellular Effects of Traumatic Stress: Implications for PTSDGirgenti MJ, Hare BD, Ghosal S, Duman RS. Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD Current Psychiatry Reports 2017, 19: 85. PMID: 28944401, PMCID: PMC5907804, DOI: 10.1007/s11920-017-0841-3.
- Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidenceHolmes SE, Girgenti MJ, Davis MT, Pietrzak RH, DellaGioia N, Nabulsi N, Matuskey D, Southwick S, Duman RS, Carson RE, Krystal JH, Esterlis I, Friedman M, Kowall N, Brady C, McKee A, Stein T, Huber B, Kaloupek D, Alvarez V, Benedek D, Ursano R, Williamson D, Cruz D, Young K, Duman R, Krystal J, Mash D, Hardegree M, Serlin G. Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 8390-8395. PMID: 28716937, PMCID: PMC5547601, DOI: 10.1073/pnas.1701749114.
- Ketamine accelerates fear extinction via mTORC1 signalingGirgenti MJ, Ghosal S, LoPresto D, Taylor JR, Duman RS. Ketamine accelerates fear extinction via mTORC1 signaling Neurobiology Of Disease 2016, 100: 1-8. PMID: 28043916, PMCID: PMC5907920, DOI: 10.1016/j.nbd.2016.12.026.
- ZNF804a Regulates Expression of the Schizophrenia-Associated Genes PRSS16, COMT, PDE4B, and DRD2Girgenti MJ, LoTurco JJ, Maher BJ. ZNF804a Regulates Expression of the Schizophrenia-Associated Genes PRSS16, COMT, PDE4B, and DRD2 PLOS ONE 2012, 7: e32404. PMID: 22384243, PMCID: PMC3288100, DOI: 10.1371/journal.pone.0032404.