Assistant Professor of Molecular and Human Genetics and Pediatrics
Appointed McNair Scholar February 2019
As a physician-scientist, my efforts are primarily focused on understanding the genetic and neuro-physiologic underpinnings of neurodevelopmental disorders such as intellectual disability, epilepsy, autism, schizophrenia and other neuropsychiatric conditions. In particular, one emerging theme in the field is that disrupted inhibitory neuronal development and function has been found in association with many neurologic and psychiatric disorders. This would be consistent with the growing body of knowledge that inhibitory neurons are highly diverse and key for virtually all aspects of neurobiology from neural circuit development to information processing. Therefore, elucidating the genetic etiologies of inhibitory neuronal development and function has great potential to advance our understanding of inhibitory neurobiology in health and disease. However, determining the genetic cause is only the first step. The critical advance needed for translation of human genetic studies into clinical applications is to identify the consequences of genetic alterations at the molecular, cellular, neural network and whole-organism levels. This mechanistic dissection of neurodevelopmental disorders bridges molecular function to disease pathogenesis, which is crucial for the development of effective targeted therapeutics. Types of genetic alterations we study in the lab impact transcriptional regulation, protein translation, cell-type specific specification. synapse formation, and neurotransmitter release.
Our goal is to determine the role of cerebro-cerebellar excitatory and inhibitory neuronal dysfunction in the pathogenesis of neurodevelopmental and neuropsychiatric disorders by deciphering how genetic alterations perturb neurotransmission in the brain, impact neural development and lead to abnormal neurologic output. In the Chao Lab, we integrate cross-species approaches in humans to uncover the genetic etiologies of neurodevelopmental disorders, fruit flies to elucidate the molecular pathways and mice to explore the cascade of events in the mammalian brain and develop pre-clinical studies. A variety of approaches and techniques are employed in our laboratory including comprehensive human phenotyping and multiomics studies, genetically engineered mouse and fruit fly models, functional analyses with electrophysiology, imaging, transcriptomics, molecular and cellular assays and behavioral profiling.
In addition to the laboratory research activities, our team leads an Epilepsy Genetics Initiative at the Duncan NRI to identify genetic determinants of undiagnosed developmental and epileptic encephalopathies and we established a multidisciplinary EBF3-related autism spectrum, ataxia, and other neurodevelopmental disorders clinic at TCH. We now follow the largest group of EBF3-related HADDS and 10q26 deletion syndrome patients to date in a single institution and conduct comprehensive phenotypic-genotypic analysis with neurocognitive profiling and neuroimaging. Finally, we are leading a Phase 0 natural history study for STXBP1-related epileptic encephalopathy with the goal of continuing to Phase 1 gene therapy studies. The findings from the clinical studies also inform our laboratory research efforts to understand how gene disruptions alter inhibitory and excitatory neuronal development, perturb neural network activity and lead to cognitive and behavioral abnormalities in neurodevelopmental and psychiatric disorders.