Development, Function and Dysfunction of Peripheral Sensory Neurons: Insights for Autism Spectrum Disorders (Smith Family Award for Excellence in Biomedical Research)
This grant is a three-year Smith Family Award for Excellence in Biomedical Research, a program of the Richard and Susan Smith Family Foundation. Autism spectrum disorders (ASD) are prevalent neurodevelopmental disorders defined by social impairments and restricted, repetitive behaviors. While ASDs are heterogeneous in etiology and severity, the majority of individuals with ASD also exhibit an array of co-morbid symptoms, including hypersensitivity to light touch and gastrointestinal dysfunction. Previously, Dr. Orefice’s laboratory used mouse models of ASD combined with behavior, anatomy, and electrophysiology to define the etiology of aberrant tactile sensitivity in ASD. They found that genetic mutations only in peripheral sensory neurons, and not neurons in the brain, account for touch over-reactivity in ASD models. Developmental touch hypersensitivity contributes to aberrant brain development, as well as anxiety and social interaction deficits in adulthood in three mouse models they studied. Selective restoration of peripheral sensory neuron function, using genetic, viral or pharmacological strategies, improves tactile hypersensitivity, anxiety-like phenotypes, and social deficits in mice. Dr. Orefice’s work has revealed a novel locus of dysfunction in ASD and how aberrant function in peripheral sensory neurons can link multiple ASD phenotypes, leading to the possibility of a therapeutic target. She will study how peripheral sensory neuron dysfunction impacts brain development, core ASD features (anxiety, social impairments), and co-morbid ASD traits (tactile hypersensitivity, gastrointestinal disturbances). She will also develop therapeutic strategies targeting peripheral sensory neurons as a tractable approach for improving ASD core and co-morbid symptoms. Dr. Orefice’s research program will iteratively combine genetics, behavior, anatomy, and electrophysiology in mice with induced pluripotent stem cell (iPSC)-based experiments. Specifically, this research will: 1) use animal models and ASD patient-derived iPSCs to study the prevalence, mechanisms and impact on brain development and behavior of peripheral somatosensory neuron dysfunction in ASD; 2) study gastrointestinal-nervous system interactions in ASD, focused on dysfunction of extrinsic spinal afferent sensory neurons; 3) develop therapies focused on peripheral sensory neuron abnormalities, using studies in mice and patient-derived iPSCs.
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