Psychiatric and Neurodevelopmental Genetics Unit
Center for Human Genetic Research
Massachusetts General Hospital
Richard B. Simches Research Center
185 Cambridge Street
Boston, MA 02114
Dr. Petryshen's research focuses on the genetic basis and treatment of major psychiatric disorders including schizophrenia, bipolar disorder, depression, and compulsive disorders. She is specifically interested in understanding how genetic changes perturb brain function and manifest as behavioral and cognitive abnormalities, and how these abnormalities can in turn be attenuated by clinical medications and novel small molecules targeting biochemical and epigenetic mechanisms implicated in psychiatric illness. Her laboratory utilizes human populations and animal and cellular model systems in combination with genetic association, behavioral neuroscience and pharmacology, biochemistry, and bioinformatic approaches.
Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium
Recent progress by large-scale genome-wide association studies (GWAS) in identifying genetic variants contributing to schizophrenia risk provides an inroad to understanding this disease. Dr. Petryshen is leading an international research consortium called GENUS that is investigating the role of psychiatric risk genes in cognitive and neuroimaging abnormalities observed in schizophrenia using a sample collection of nearly 10,000 cases and controls. The objective is to elucidate the function of schizophrenia genetic risk variants in neural circuits and mechanisms underlying this disease.
This research is supported by the National Institute of Mental Health (NIMH) under award number R01MH092380.
Role of the Bipolar Disorder Risk Gene Ankyrin 3 in Brain and Behavior
Ankyrin 3 (ANK3) has been identified in large-scale genome-wide association studies (GWAS) as one of the most significant risk genes for bipolar disorder. ANK3 encodes the ankyrin G scaffolding protein, which has many essential functions in the brain, including maintenance of the neuron axon initial segment where action potentials are generated. However, the mechanism by which ANK3 confers susceptibility to bipolar disorder is unknown. This project uses novel molecular and behavioral neuroscience tools, proteomic analyses, and transgenic and cellular models to gain a better understanding at both the phenotypic and cellular levels of the function of ankyrin 3 in brain and behavior in normal and disease states. Results from these studies are expected to advance current understanding of the role of ankyrin 3 in the brain, and may contribute insight into the genetic bases of neural dysfunction at the core of bipolar disorder. This research is supported by the National Institute of Mental Health (NIMH) under award number R21MH100570 and the Stanley Medical Research Institute.
Targeting GSK3 for Treatment of Major Depressive Disorder
Major depressive is a disabling mood disorder affecting approximately 16% of the population. One-third of patients do not respond to current medications, highlighting the critical need for new treatments with alternative mechanisms of action. Glycogen synthase kinase 3 (GSK3) signaling has been implicated as a promising novel target for depression treatment. We and others have shown that treating mice with small molecule inhibitors of GSK3 improves behaviors conventionally used to gauge antidepressant efficacy (Pan et al. Neuropsychopharm 2011). We are collaborating with colleagues in the CHGR and the Broad Institute who are identifying potent and selective inhibitors of GSK3 in biochemical and cellular assays that we are evaluating for antidepressant activity in mouse models. The goal of this research is to obtain compelling evidence for the significance of GSK3 in depression treatment and to identify novel inhibitors for translation into human proof-of-concept clinical trials.
This research is supported by the Avis and Clifford Barrus Medical Foundation.
Preclinical Studies of Glutamatergic Treatments for Pediatric Compulsive Disorders
Compulsive disorders such as obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS) are characterized by uncontrollable, repetitive, and ritualized behaviors that typically onset during childhood and do not respond well to current treatments. A disruption in glutamatergic frontrostriatal neurotransmission is thought to underlie compulsive behaviors. As part of the Translational Adolescent and Childhood Therapeutic Interventions in Compulsive Syndromes (TACTICS) international consortium, we are investigating whether drugs that reduce glutamate signaling attenuate compulsive symptoms in a juvenile mouse model of compulsive disorders that is disrupted for the Slitrk5 gene, which is thought to function in neurite outgrowth and synaptic formation. This research is expected to obtain evidence for the use of glutamatergic agents for treatment of compulsive disorders in children, which will support clinical trials in pediatric populations conducted by collaborators in the TACTICS consortium.
Other members of the SLITRK gene family have been implicated in compulsive disorders, specifically SLITRK1 and SLITRK6 that were identified in Tourette Syndrome patient genetic studies and a GWAS led by PNGU colleague Dr. Jeremiah Scharf. We are evaluating the function of genetic variants in the SLITRK6 gene identified by Dr. Scharf, including a SNP that disrupts a putative a transcriptional co-activator binding site that is active in neurons based on evidence from the Encyclopedia of DNA Elements (ENCODE) project. Using human neural progenitor cells derived from induced pluripotent stem cells (iPSCs), we are studying whether the risk allele of this SNP alters transcriptional activity and gene expression, which could theoretically alter brain function and contribute to the development of TS.
This research is funded by the European Commission under an FP7-HEALTH-2011 award “Translational Adolescent and Childhood Therapeutic Interventions in Compulsive Syndromes (TACTICS)” (PI: Dr. Jan Buitelaar), and formerly funded by a National Institute of Mental Health (NIMH) T32 training fellowship to the Stuart T. Hauser Clinical Research Training Program (Co-PIs: Drs. Martha Shenton, Robert McCarley, Gail Musin).
Investigating the Mechanisms of Clinical Medications to Identify Novel Targets for Developing New Treatments
We are involved in a number of collaborative studies investigating the mechanisms of action of clinical medications through biochemical, molecular, and behavioral analysis of cellular and mouse models to identify novel targets for the development of new treatments. Small molecule compounds identified in cell-based screens against these novel targets are optimized and subsequently evaluated by our group in preclinical mouse assays that predict treatment efficacy in patients, followed by further medicinal chemistry optimization and preclinical testing. The preclinical results provide evidence for the relevance of these targets to disease and support the advancement of promising compounds into clinical trials.
Mai Saito, BSc
Title: Senior Research Technician
Education: BSc in Animal Science, Pre-vet, University of Hawaii, Hilo, HI
Gabriëlla Blokland, MSc, MSc, PhD
Title: Postdoctoral Research Fellow
Education: MSc in Psychology and Health, Tilburg University, Netherlands
MSc in Neurosciences, VU University, Netherlands
PhD, Queensland Institute of Medical Research, Australia
Jacob Garza, MSc, PhD
Title: Postdoctoral Research Fellow
Education: MSc in Biology, Texas A&M University, Kingsville TX
PhD, University of Texas Health Science Center at San Antonio
Klaudio Gjeluci, BSc
Title: MSc Student
Education: BSc, University of Massachusetts Boston, Boston MA
Kelly Dennehy, BA
Title: Research Technologist
Education: BA in Psychology, University of Nevada, Las Vegas NV
Title: Undergraduate Intern
Education: Emmanuel College, Boston MA
Sarah Bergen, MS, PhD
Erin Berry-Scott, BSc
Santina Caruso, BSc
Elizabeth Clore, BSc
Jorgen de Haan, PhD
Melanie Leussis, PhD
Michael Lewis, PhD
Al Schroeder, PhD
Prachi Thanawala, BSc
Haiyan Wang, MD, MSc
Margaret Wey, Ph.D.
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