Rakesh Karmacharya, MD, PhD
Dr. Karmacharya is working at the intersection of chemical biology and stem cell biology to investigate the cellular-molecular underpinnings of schizophrenia and bipolar disorder. He received an A.B. in Biochemistry from Harvard, an M.S. in Molecular Biophysics from Yale, and an M.D. and a Ph.D. in Biophysics from the Albert Einstein College of Medicine. After his clinical training, he undertook postdoctoral studies in chemical biology under the mentorship of Prof. Stuart Schreiber.
Research in the Karmacharya laboratory uses approaches at the intersection of chemical biology and stem cell biology in order to investigate cellular pathways relevant to neurodevelopment and to neuropsychiatric disorders. A major project in the lab involves the identification of disease signatures for schizophrenia, bipolar disorder and autism using patient-derived cells generated from induced pluripotent stem cells (iPSCs). We differentiate human iPSCs to cortical neurons, interneurons, astrocytes, microglia and brain microvascular endothelial cells in order to identify disease-related differences in specific neuronal and glial subtypes. We also differentiate iPSCs to generate three-dimensional cerebral organoids to investigate disease-related functional features, utilizing multi-electrode arrays and Seahorse assays. We undertake studies under basal conditions, as well as in the presence of perturbations with sets of annotated small molecules, in order to uncover disease-related vulnerabilities in specific cellular pathways. We couple these studies with phosphoproteomic, metabolomic and gene-expression studies to delineate the nature of cellular process that are aberrant in disease. We are interested on how environmental effects, such as inflammation, affects brain development, in the context of normal brain development or in the setting of disease genetic background. We seek to develop an ex vivo model of effects related to maternal immune activation in human neurodevelopment. By exposing growing cerebral organoids to specific inflammatory cytokines, we are studying how exposure during specific developmental windows to specific cytokines affects the functioning of organoids at nine months of age. We are also interested in developing new small-molecule potentiators of neuronal activity-dependent induction of Arc (Activity-regulated cytoskeleton-associated protein; Arg3.1) and investigate their effects on synaptic biology in human cortical neurons, in order to develop small molecules with pro-cognitive potential.
Questions being addressed in the lab
Projects underway to answer these questions
Highlighted Publications from the lab
HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells