Damage to or loss of the peripheral axons of primary sensory neurons is associated with two clinical syndromes: peripheral neuropathic pain and peripheral neuropathy. Treatment for neuropathic pain is typically ineffective or associated with side effects, and there is no treatment for peripheral neuropathy. To remedy this, it is essential that the mechanisms responsible for both are understood and targets identified that could be amenable to development of novel therapeutics. My goal is to dissect out at an individual neuron level the transcriptional and functional changes that occur over time in response to physical axonal injury, ion channel mutations and exposure to neurotoxic cancer chemotherapeutic agents, and explore the extent to which hyperexcitability and axon degeneration are linked. This will involve combinations of several different approaches: correlating single cell profiles and disease related functional changes, identifying disease susceptibility in patient stem derived neurons, high content phenotypic screens, population imaging in intact animals, genetic editing, and interrogation at high temporal and spatial resolution of behavioral surrogates of pain and sensory loss. The project will focus on neuropathic pain due to physical disruption of peripheral sensory axons, small fiber neuropathies due to voltage-gated sodium channel mutations and chemotherapy- induced peripheral neuropathy, and will examine if these syndromes are distinct or part of a spectrum of sensory neuron pathologies with overlapping risk factors and mechanisms.

Public Health Relevance

This project is designed to identify the molecular and cellular changes that occur in sensory neurons after axonal injury and establish how these drive neuropathic pain and the evolution of peripheral neuropathy, exploring the extent to which these two syndromes are distinct or linked, and identifying opportunities for new therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Unknown (R35)
Project #
5R35NS105076-02
Application #
9612591
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Oshinsky, Michael L
Project Start
2017-12-15
Project End
2025-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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