Chemical Genomics of Neuropsychiatric & Neurological Disease

Overview

Our multidisciplinary research program involves a combination of approaches including synthetic chemistry, neuroscience, and human genetics. Using this chemical-genomic approach, members of our research group invent new methods for finding small-molecule probes that target key components of the neurocircuitry, and then use these probes to selectively perturb neuronal network function at the molecular, cellular and circuit level. As a result of our work, we hope to develop novel, targeted therapeutics for treating neuropsychiatric disorders, including bipolar disorder, depression, schizophrenia, fragile X syndrome, and neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease. We conduct this research program in close collaboration with other members of the Center for Human Genetic Research (CHGR) at MGH and the Stanley Center for Psychiatric Research. We are also affiliated with the Harvard Stem Cell Institute (HSCI).

Our studies entail three general types of experimental approaches:

Small-Molecule Probe Discovery & Proteomic Characterization

Cellular and biochemical assays for screening small molecules, RNAi, and cDNA libraries are developed in order to enable discovery of agents targeting disease-relevant mechanisms and pathways identified by human genetics. Identification of targets and functional characterization of new molecular probes is performed using proteomic methods.

Neural Stem Cell-Based Models

Neural stem cells, including induced pluripotent stem (iPS) cells from reprogrammed somatic cells, are being developed for characterizing the function of disease genes and pathways. These cell lines will eventually provide genetically accurate models for high-throughput chemical screening.

In Vivo Animal Models

Small-molecule probes employing new mechanism of action are tested in animal behavioral models relevant to mood and memory disorders through collaborations with a variety of investigators interested in the development of novel therapeutics.

Group Members

Mass General Center for Human Genetic Research

Director, Chemical Genomics of Neuropsychiatric and Neurological Disease Program

Stephen Haggarty, PhD

Research Scientists

Surya Reis, PhD
Krista Hennig, PhD
Chialin Cheng, PhD

Research Technicians

Iren Kurtser, MSc
Stephanie Norton, BSc
Kraig Theriault, BSc

Broad Institute - The Stanley Center for Psychiatric Research

Director, Chemical Genomics of Neuropsychiatric and Neurological Disease Program

Stephen Haggarty, PhD

Research Scientists

Dan Fass, PhD
Jen Pan, PhD
MJ Kim, PhD
John Madison, PhD

Research Technicians

Josh Ketterman, MSc
Xiulin Liu, MSc
Catherine Luce, MSc

Research Projects

Chromatin-Mediated Neuroplasticity in Memory and Mood

The role of chromatin-modifying enzymes in regulating transcriptional programs important to memory and mood are being investigated. Efforts to develop CNS penetrant, isoform selective inhibitors of class I/class II histone deacetylases (HDACs) and histone demethylases implicated in neuroplasticity and testing of these probes in vivo using behavioral models are underway.

GSK-3/β-Catenin in Neurotransmission

The role of GSK-3/ β-catenin in regulating pathways important to neuropsychiatric disease is being investigated. Inhibitors of GSK-3 are being tested in animal models of behavior and efforts to develop CNS penetrant, allosteric, ATP non-competitive inhibitors of GSK-3β through medicinal chemistry are underway. A collection of small-molecule modulators of GSK-3/β-catenin signaling have been identified through a panel of cell-based, high-throughput screens and the relevant targets are being identified using RNAi and proteomics.

Neural Stem Cell Models of Mental Illnesses

Genetically accurate neural stem cell models of mental illness are being developed in collaboration with the Harvard Stem Cell Institute and our genetics collaborators in Dr. Pamela Sklar’s laboratory at MGH. Patient-derived somatic cells with specific genomic abnormalities and haplotypes are being reprogrammed into induced pluripotent stem (iPS) cells to enable discovery of disease-associated phenotypes as the basis for small molecule and RNAi screens as well as functional studies of these disease mechanisms.

Chemical Modulators of Neurotoxicity and Neurodegeneration

Small-molecule modulators of aberrant cell-cycle activity and DNA damage associated with neurodegeneration implicated in Alzheimer’s disease and LRRK2-mediated neurodegeneration implicated in Parkinson’s disease are being developed using cell-based and biochemical approaches.

Research Positions

Postdoctoral Fellow/Research Scientist Positions

The Haggarty Laboratory seeks highly motivated individuals to work in the area of chemical genomics of neuropsychiatric and neurological disorders. This is a unique opportunity for working in a fast-paced, and highly collaborative, translational research group working at the interface of chemistry, biology, and therapeutic development.

Qualifications

MD and/or PhD in neurobiology, molecular biology, chemistry, or related field required. Must posses familiarity with mammalian cell culture, fluorescence microscopy, and molecular biology. Must posses excellent computer skills and ability to perform basic quantitative analysis of large data sets. Knowledge of programs such as Spotfire, PipelinePilot and GeneData would be preferred. More advanced statistics or programming skills a plus. Excellent critical thinking skills and attention to detail needed. Must be able to use sound judgment to effectively solve problems, work independently, and handle a variety of tasks. Requires effective oral and written communication skills along with meticulous laboratory technique and recording skills. Must be able to use discretion to organize workflow and to change methodologies to optimize work results and communicate effectively with all levels of staff to ensure that work supports team goals.

Interested applicants should send curriculum vitae and names of three references via email or postal mail to:

Stephen Haggarty, PhD
Center for Human Genetic Research
Massachusetts General Hospital
185 Cambridge Street
Boston, MA 02114 USA
e-mail:haggarty@chgr.mgh.harvard.edu

Undergraduate Students/Medical School Students

Students interested in a rotation or thesis project should contact Dr. Stephen Haggarty directly by emailhaggarty@chgr.mgh.harvard.eduwith a copy of their curriculum vitae and a statement of their research interest. Limited fellowships are available. Regretfully, we do not have the resources to support all applicants who apply.

Publications