Stephen J. Haggarty, Ph.D., is
an Assistant Professor of Neurology at Harvard
Medical School, an Assistant in Neuroscience
at Massachusetts General Hospital’s
Center for Human Genetic Research, the Director
of Chemical Neurobiology at the Stanley
Center for Psychiatric Research, and an
Associate member of the Broad Institute
of Harvard and MIT. Dr. Haggarty received
his Ph.D. from Harvard University. Dr. Haggarty
then joined the Broad Institute as a research
Fellow in the Chemical Biology Program and
became a founding member of the Stanley
Center for Psychiatric Research. Dr. Haggarty’s
overall research program combines the use
of chemistry and genetics to develop novel
therapeutics for central nervous system
disorders.
Overview
The Chemical Genomics Laboratory (CGL) aims
to illuminate the molecular mechanisms underlying
neuroplasticity in order to develop novel,
targeted therapeutics for the treatment
of neuropsychiatric and neurological disease.
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, schizophrenia,
fragile X syndrome, and Rett syndrome. We
are also engaged actively in collaborations
developing probes for neurodegenerative
disorders. 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).
Projects in the lab are focused in three
main areas:
I. 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.
II. GSK-3/ß-Catenin in Neurotransmission
The role of GSK-3/ß-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-3ß
through medicinal chemistry are underway.
A collection of small-molecule modulators
of GSK-3/ß-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. Testing of these probes
in vivo using behavioral models are underway.
III. 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 and clinical
collaborators at MGH and around the world.
Patient-derived somatic cells with specific
genetic abnormalities are being reprogrammed
into induced pluripotent stem (iPS) cells
to enable investigation of disease pathogenesis
and functional studies of candidate genes.
A subset of the phenotypes being identified
are serving as the basis for developing
high-throughput small molecule and RNAi
screens aiming to identify novel therapeutic
mechanisms and targets. To date, iPS cell
models for monogenic disorders (fragile
X syndrome, fragile X-associated tremor/
ataxia syndrome, Rett disorder) and polygenic
disorders (bipolar disorder) have been developed.
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