ChemicaChemical neurobiology of neuropsychiatric disorders: We use chemical biology along with molecular and cell biology approaches to understand how the nervous system functions in health and disease. We are particularly interesteinterested in the molecular mechanisms of neuroplasticity and how these are affected in psychiatric and neurodegenerative disorders and may be targeted therapeutically.
Center for Human Genetic Research
Massachusetts General Hospital
185 Cambridge Street, CPZN-5242
Boston, MA 02114
The focus of the Haggarty Laboratory is on the use of chemical biological approaches to define and dissect the role of neuroplasticity in health and disease. Our long-term goal is to translate this knowledge into the discovery of novel, disease mechanism-based, targeted therapeutics for the treatment of psychiatric and neurodegenerative disorders.
Members of the lab have developed powerful, in vitro experimental systems in which populations of defined neuronal subtypes belonging to specific neurotransmitter classes and regional identities with the ability to form synapses and electrically active, neural networks, can be directly identified, manipulated pharmacologically and genetically, and characterized using functional genomics, proteomics, and high-throughput screening modalities. This has lead to the discovery, characterization, and optimization of novel chemical probes of critical neuroplasticity mechanisms—the regulation of neurotrophic factor signaling, the epigenetic regulation of neuronal gene expression through histone deacetylases (HDACs) and histone demethylases (HDMs), and the regulation of Wnt/GSK3 signaling. To address the challenge of target identification, we have also integrated the use of systematic RNAi-mediated gene silencing and quantitative mass spectrometry strategies. In order to explore new directions for human disease modeling, we have most recently implemented reprogramming methods for creating induced pluripotent stem cells (iPSCs) and induced neurons (iNs) from patient-derived somatic cells. These iPSCs can be differentiated in vitro into functional neurons with the capacity to form synapses and regulate genes in an activity-dependent manner opening new avenues for chemical genomic studies of neuroplasticity and for understanding human disease biology. Current projects include the development, characterization and screening of human iPSC models of neuropsychiatric (bipolar disorder, schizophrenia, Pitt-Hopkins Syndrome, Rett Syndrome, Fragile X Syndrome) and neurodegenerative disorders (Alzheimer’s Disease and Frontotemporal Dementia), all of which aim to establish novel paradigms for target identification and discovery of small-molecule probes. Finally, we are investigating the in vivo effects of a number of our novel small-molecule probes using animal behavioral models relevant to cognitive and mood disorders, as well as with positron emission tomography to image targets and neural activity in the context of intact neurocircuits.
We conduct our research program in close collaboration with other members of the Harvard and MIT research community, including the MGH Molecular Neurogenetics Unit, MGH Psychiatric & Neurodevelopmental Genetics Unit, MGH Center for Experimental Drugs & Diagnostics, Lurie Center for Autism, Stanley Center for Psychiatric Research at the Broad Institute, and the Harvard Stem Cell Institute.
Haggarty, S.J. & Tsai, L.H. (2011). Probing the role of HDACs and mechanisms of chromatin-mediated neuroplasticity. Neurobiology of Learning & Memory, 96: 41-52.
Fass, D.M., Shah, R., Ghosh, B., Hennig, K., Norton, S., Zhao, W.N., Reis, S., Klein, P., Mazitschek, R., Maglathlin, R., Lewis, T. & Haggarty, S.J. (2011). Effect of inhibiting histone deacetylase with short-chain carboxylic acids and their hydroxamic acid analogs on vertebrate development and neuronal chromatin. ACS Medicinal Chemistry Letters, 2:39-44.
Pan, J.Q., Lewis, M.C., Ketterman, J.K., Clore, E.L., Riley, M., Richards, K.R., Berry-Scott, E., Liu, X., Wagner, F.F., Holson, E.B., Neve, R.L., Biechele, T.L., Moon, R.T., Scolnick, E.M., Petryshen, T.L. & Haggarty, S.J. (2011). AKT kinase activity is required for lithium to modulate mood-related behaviors in mice. Neuropsychopharmacology, 36:1397-1411.
Kuai, L, Ong, S.E., Madison, J.M., Wang, X, Duvall, J.R., Lewis, T.A., Luce, C.J., Conner, S.D., Pearlman, D.A., Wood, J.L., Schreiber, S.L., Carr, S.A., Scolnick, E.M. & Haggarty, S.J. (2011). Identification of AAK1 as an inhibitor of neuregulin-1/ErbB4-dependent neurotrophic factor signaling using integrative chemical genomics and proteomics. Chemistry & Biology, 18:891-906.
Covington, H.E., Maze, I.S., LaPlant, Q.C., Vialou, V.F., Yoshinori, O.N., Berton, O., Fass, D.M., Renthal, W., Rush, A.J., Wu, E.T., Ghose, S., Krishnan, V., Russo, S.J., Tamminga, C., Haggarty, S.J. & Nestler. E.J. (2009). Antidepressant actions of HDAC inhibitors. Journal Neuroscience, 29:11451-11460.