Candidate: I am a postdoctoral fellow in Dr. David Ginty's laboratory at Harvard Medical School. My research interests include using basic biomedical research to study the mechanisms of dysfunction in Autism Spectrum Disorders (ASD) and developing translational strategies for novel potential therapeutic approaches. I have used a range of mouse ASD genetic models combined with behavioral testing, anatomy, and synaptic analyses to define both the etiology of aberrant tactile sensitivity in ASD and the contribution of peripheral somatosensory neuron dysfunction to the expression of ASD-like traits (Orefice et al., Cell, 2016). Environment: Research will be conducted at Harvard Medical School (HMS) under the mentorship of Dr. Ginty, a leader in the field of somatosensory neurobiology. Dr. Ginty has an excellent mentorship record, with 13 of his past 14 postdoctoral fellows now in faculty positions at leading research universities. The co- sponsors, also at HMS, are all well-established scientists with excellent publication and training records in neuroscience and expertise in the techniques proposed in this training plan. Career Development: Training activities will include the mastery of electrophysiological techniques by performing experiments and attending workshops/courses, including an intensive 3-week `Ion Channels in Synaptic and Neural Circuit Physiology' course at Cold Spring Harbor. I will also attend scientific meetings focused on ASD and somatosensory biology. Third, I will acquire skills for applying basic research to potential therapeutic applications. Finally, I will hone skills required for managing an independent laboratory. Currently, I mentor two undergraduates and provide guidance to several graduate students for mentorship experience. Research Plan: My recent work revealed a locus of dysfunction underlying aberrant tactile perception in ASD that was surprisingly outside the brain. I found that developmental dysfunction of peripheral somatosensory neurons at their synapses within the spinal cord results in abnormal tactile processing and is a major contributor to anxiety-like behavior and social interaction deficits in adult Mecp2 and Gabrb3 mouse models of ASD. This application will utilize behavior, histology and electrophysiology to extend these preliminary findings in new basic research directions and toward the development of novel therapeutic strategies. During the K99 phase, I will determine whether peripheral somatosensory neuron deficits are a common cause of dysfunction in other models of ASD (Shank3, Fmr1) (Aim 1). Second, I will identify peripherally acting gene therapies and small molecule therapeutics to treat tactile hypersensitivity in ASD mouse models, with the goal of alleviating somatosensory, anxiety-like and social interaction deficits (Aim 2). The focus of the R00 phase will be to continue therapeutic development as started in Aim 2 and to use electrophysiology, anatomical tracing and in vivo imaging to understand how peripheral somatosensory dysfunction affects brain development and ultimately leads to anxiety-like behavior and social interaction deficits in ASD mouse models (Aim 3).

Public Health Relevance

Autism spectrum disorders (ASD) are a highly prevalent (1 in 68 children) class of neurodevelopmental disorders characterized by impairments in social communication and interactions, restricted/repetitive behaviors and abnormal responses to sensory stimuli. The goal of this proposal is to elucidate how the peripheral somatosensory system and spinal cord processing of sensory information are affected in ASD. Because of the relative ease of accessibility of the peripheral nervous system, insights gleaned from our proposed studies may lead to opportunities for therapeutic approaches for the treatment of hypersensitivity or aversion to social touch, as well as the abnormal development of social behaviors and nervous system function in ASD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Transition Award (R00)
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NST-2 Subcommittee (NST)
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Mamounas, Laura
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Massachusetts General Hospital
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