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.
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.
|Cronin, Shane J F; Seehus, Corey; Weidinger, Adelheid et al. (2018) The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature 563:564-568|
|Liu, Yuanyuan; Latremoliere, Alban; Li, Xinjian et al. (2018) Touch and tactile neuropathic pain sensitivity are set by corticospinal projections. Nature 561:547-550|
|Latremoliere, Alban; Cheng, Long; DeLisle, Michelle et al. (2018) Neuronal-Specific TUBB3 Is Not Required for Normal Neuronal Function but Is Essential for Timely Axon Regeneration. Cell Rep 24:1865-1879.e9|
|Cobos, Enrique J; Nickerson, Chelsea A; Gao, Fuying et al. (2018) Mechanistic Differences in Neuropathic Pain Modalities Revealed by Correlating Behavior with Global Expression Profiling. Cell Rep 22:1301-1312|