Psychiatric and Neurodevelopmental Genetics Unit
Center for Human Genetic Research
Massachusetts General Hospital
Richard B. Simches Research Center
185 Cambridge Street
Boston, MA 02114
The focus of Dr. Petryshen's research is the etiology and treatment of multi-factorial psychiatric and behavioral disorders through patient and mouse genetic studies, and mouse behavioral pharmacology studies.
Dr. Petryshen has been involved in numerous studies to identify and characterize candidate genes for schizophrenia and bipolar disorder encompassing linkage, haplotype-based gene association, population genetic, and microarray mRNA expression methods. She is currently focused on investigating the role of psychiatric risk genes in regulating brain function through genetic association studies of intermediate phenotypes (endophenotypes) in patient populations. Her translational human and mouse research encompasses examining risk genes identified in patient genetic studies using powerful tools such as in vivo mouse brain RNA interference and transgenic models to determine the effect of gene expression and allelic changes at both the phenotypic and cellular levels. In addition, her lab utilizes mouse behavioral, biochemical, and molecular methods to investigate the mechanisms of clinical medications and the therapeutic potential of novel small molecules targeting biochemical pathways and epigenetic mechanisms implicated in psychiatric illness.
- Genetics of Vulnerability to Schizophrenia Progression
Schizophrenia (SCZ) is a devastating illness characterized by progressive decline in neurocognition and brain function that seriously impair daily functioning and patient outcome, and are not improved by current medications. This project is investigating the genetic contribution to post-onset functional deterioration in SCZ by performing a genetic association study of SCZ subjects and matched controls across prodromal, first episode and chronic disease stages who are assessed for cognitive, neuroimaging (structural MRI, DTI), electrophysiological, and hormonal phenotypes that are abnormal in patients and decline over the course of disease. Investigation focuses on genetic variants implicated in SCZ risk by genome-wide association studies (GWAS), including single nucleotide polymorphisms (SNPs), copy number variants (CNVs; chromosomal deletions and duplications), and polygenic factors (thousands of SNPs with negligible individual effect that in aggregate contribute disease risk). The project is a component of an NIMH-funded P50 Center for Intervention Development and Applied Research (CIDAR; www.bostoncidar.org) involving PNGU faculty Dr. Shaun Purcell and investigators from the Boston VA Healthcare System, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, and McLean Hospital. Funded by the NIH/NIMH and by the MGH Executive Committee on Research.
- Role of the Bipolar Disorder Risk Gene Ankyrin 3 in Behavioral Regulation
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 (BD), a severe mood disorder characterized by manic and depressive episodes for which the etiology is just beginning to be unraveled. 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 BD is unknown. This project aims to gain a better understanding of the function of ankyrin 3 in brain function through complementary studies of behavior, pharmacological response, and neural and synaptic activity. Results from these studies are expected to advance current understanding of the role of ankyrin 3 in brain function, and may contribute insight into the genetic bases of neural dysfunction at the core of BD. Funded by the Stanley Medical Research Institute.
- Mouse Genetics of Prepulse Inhibition
Prepulse inhibition (PPI) is a neural information processing system that is impaired in many psychiatric disorders including schizophrenia and bipolar mania, and that is related to higher order cognition. This study is utilizing mouse genetic mapping and molecular approaches to identify genes regulating PPI that may also contribute to psychiatric and cognitive disorders.
- Targeting GSK3 for Treatment of Major Depressive Disorder
Major depressive disorder (MDD) 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 MDD 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 chemically modifying lead GSK3 inhibitor compounds to optimize their drug-like properties, and identifying the most potent and selective inhibitors in biochemical and cellular assays that we are evaluating for antidepressant activity in mouse behavioral and transgenic models. The goal of this research is to obtain compelling evidence for the significance of GSK3 in MDD treatment and to identify novel inhibitors for translation into human proof-of-concept MDD trials. Supported by the Avis and Clifford Barrus Medical Foundation for Research on Depression in Women.
- 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. Treatment options are limited, and a large proportion of patients do not respond to current treatments. A disruption in glutamatergic frontrostriatal neurotransmission is thought to underlie compulsive behaviors, which is supported by open labels clinical trials suggesting a beneficial effect of glutamate-modulating agents in adult OCD. However, double blind clinical trials have not yet been conducted, and glutamatergic agents have not been evaluated in pediatric populations when the disorders emerge. 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. 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. Supported by the European Commission.
- 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 behavioral 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: Research Technician
Education: BSc in Animal Science, Pre-vet, University of Hawaii, Hilo
Title: MSc Student
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
Foreign students and postdoctoral fellows are encouraged to contact Dr. Petryshen to discuss research training and funding opportunities.
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