The human brain is capable of remarkable feats of experience-dependent plasticity that enable it to consistently adapt to a changing environment, to learn, and to form stable memories that can guide future behavior. Growing evidence suggests that these mechanisms of neuroplasticity are disrupted in the case of brain disorders and upon the natural process of aging. To better understand these mechanisms and to provide novel therapeutics, our laboratory is developing and applying innovative strategies and technologies for the systematic identification and targeting of the underlying molecular, cellular, and circuit-level mechanisms that regulate neuroplasticity in the central nervous system (CNS). Through probing the mechanisms of neuroplasticity that are critical for health and disease with novel experimental therapeutics, we expect that our studies, in conjunction with emerging evidence from human genetics, will improve our understanding of neuropsychiatric and neurodegenerative disorders and through translational efforts will lead to the development of targeted therapeutics for their prevention and treatment.
- Our work has contributed to the recognition of the critical role of epigenetic mechanisms in brain health and disease, which present a whole host of novel therapeutic strategies based upon altering aberrant states of gene expression and chromatin structure.
- We have also developed novel screening approaches using patient-derived stem cell models that enable the investigation of the neuroplasticity and neuropharmacology using human neurons—a feat not previously achievable due to the difficulty of accessing living human neurons that now opens many new avenues for small molecule discovery.
- We are testing our hypotheses both in pre-clinical animal models of memory and mood disorders and in on-going experimental therapeutic trials in patients with our colleagues in the MGH Department of Psychiatry and MIT Picower Institute of Learning & Memory.
I) Small-Molecule Probes Targeting Epigenetic Mechanisms
CREB Pathway Project: Cell-based assays of CREB-mediated transcription
Histone Lysine Acetylation Project: Selective HDAC Inhibitors/Activators // Selective CBP HAT Activators
Histone Methylation Project: Selective LSD1 Inhibitors
II) Generation & Characterization of Patient-Specific Stem Cell Models
Neuropsychiatric Disorders: Fragile X syndrome // Rett Syndrome // Pitt-Hopkins Syndrome // Bipolar Disorder
Neurodegenerative Disorders: Tauopathies // Alzheimer’s Disease // Frontotemporal Dementia
III) Functional Genomics & Biochemistry of Neuropsychiatric Disorders
WNT Pathway: GSK3 // DISC1 // DVL1
Actin Cytoskeleton Remodeling: GIT1
Systematic RNAi Screening