CHEMICAL GENOMICS OF NEUROPSYCHIATRIC DISORDERS

The long-term goal of the Haggarty laboratory is to advance the discovery of novel targets and therapeutic agents for the treatment of cognitive and mood disorders using translational neurobiology and the principles of network medicine. These efforts are guided by and inform the knowledge emerging from human genetics of the root causes of neuropsychiatric disorders. We are also leveraging transformative advances in the fields of neuroscience, stem cell biology, and chemical biology that collectively enable an unprecedented opportunity to probe the molecular, cellular and circuit level mechanisms of neuroplasticity in health and disease. Using this chemical genomic strategy we have be able to investigate the response of mouse and human neurons cells to thousands of different chemical probes leading to the discovery, characterization, and optimization of novel chemical probes of critical neuroplasticity processes—the regulation of neurotrophic factor signaling through BDNF/TrkB, the epigenetic regulation of neuronal gene expression, synaptogenesis, the regulation of WNT/GSK3 signaling, and protein homeostasis.

Neuroepigenetic Mechanisms & Chromatin Biology
A major interest continues to be to dissect the role of epigenetic mechanisms in the regulation of chromatin-mediated neuroplasticity. These neuroepigenetic mechanisms involve neural substrates that acts as critical mediators of cognitive and mood processes. Based upon discoveries in animal models measuring memory formation, as well as in behavioral models relevant to mood, we continue to dissect the underlying biochemistry and pharmacology of different chromatin-modifying complexes involved in the dynamic regulation activity-dependent gene expression and the formation and maintenance of synapses. On-going projects include the development small-molecule probes and functional genomic tools to systematically target key neuroepigenetic mechanisms and to connect these process to human disease where mutations may disrupt epigenetic regulation in the CNS in the context of dementia, schizophrenia, and neurodevelopmental disorders.

Genes & Networks Underlying Neuroplasticity
Related to the objective of identifying novel targets for cognitive and mood disorders, we have developed powerful, genome-wide functional genomic and chemical screens in rodent neurons to discover novel genes, networks, and chemical probes that regulate neuroplasticity. In addition to investigating the mechanisms through which the BDNF/TrkB neurotrophic pathway impacts synaptic plasticity and connecting his pathway to genes implicated in the etiology of neuropsychiatric disorders, we also investigate the role of WNT/GSK3 signaling as a pathway involved in neurodevelopment and neuroplasticity. In the latter case, we have recently performed one of the largest ever human stem cell-based, high-throughput screens leading to novel modulators of WNT/GSK3 signaling networks that can control neurogenesis and pathways critical to neuroplasticity in human neurons. Collectively, the novel targets and novel compounds discovered by these screens are being investigated using integrative functional genomic and proteomic strategies as well as being advanced toward in vivo using animal models to probe memory and mood neurocircuits.

Human Stem Cell Models for Precision Medicine
Lastly, to advance a platform for precision medicine to support studies of human disease biology and the discovery of next-generation neuropharmacological agents, a major emphasis is on the use of reprogramming technology to create patient-specific, induced pluripotent stem cell (iPSC) and induced neuron (iN) models of neuropsychiatric disorders in conjunction with CRISPR/Cas genome editing methodologies. The ability to differentiate these human iPSCs or iNs in vitro into electrically active, functional neural networks with the capacity to form synapses and regulate genes in an activity-dependent manner provides powerful ex vivo systems for studies of neuroplasticity, for understanding the neurobiology of human disease, and for discovering novel targets for therapeutic development. Along with our clinical collaborators, to date we have generated one of the largest panels of patient-specific iPSC from individuals with monogenic neurodevelopmental disorders caused by highly penetrant mutations (e.g. Fragile X syndrome, Pitt-Hopkins syndrome, Tuberous sclerosis), as well as monogenic neurodegenerative disorders (e.g. frontotemporal dementia due to MAPT (Tau) or GRN (progranulin) mutations), and from genetically complex disorders (e.g. bipolar disorder, schizophrenia). With the panel patient-specific models we are now well position able to identify points of convergence amongst neuropsychiatric disorders and develop innovative new screening strategies for their treatment and prevention using the principles of network medicine.