Thursday, November 21, 2024
11/21/2024
ABSTRACT Voltage-gated sodium channels (VGSCs) are critical gatekeepers of nociceptor excitability. In nociceptors, VGSCs are required for nociception, chronic pain, and their increased function causes pain without injury. Most of our knowledge of VGSCs in nociceptors and their alterations in chronic pain come from rodent and heterologous expression system studies. However, emergent studies on human dorsal root ganglia reveal prominent species differences in VGSC expression, kinetics, pharmacology, and modulation. Thus, the premise of this study is to thoroughly characterize unique sodium currents biophysics in human dorsal root ganglia (DRG) neurons, which will identify novel therapeutic targets and lead to the development of nonopioid analgesics. Our recent spatial sequencing studies revealed that β4 is highly expressed in all human dorsal root ganglia neurons but, in mice, confined to large-diameter neurons and C-low threshold mechanoreceptors, which are generally non-nociceptive. Half of large-diameter, but not small-diameter (generally nociceptive), murine DRG neurons exhibited resurgent current. This strongly suggests that human nociceptors generate resurgent currents. Focusing on interactions between VGSCs and their known modulators, I will determine whether human nociceptors display resurgent sodium currents, if resurgent currents are potentiated by nociceptor sensitization, and if they are driven, at least in part, by intracellular interactions between VGSCs and NAVβ4 and/or FGFs. In nociceptors, resurgent sodium currents may dramatically increase neuronal activity by augmenting spontaneous activity, evoking persistent current, and mediating repetitive firing. In the context of pain, resurgent sodium currents may convert mild nociceptor activation to trains of action potentials that can provoke intense pain and lead to activity-dependent plasticity in central synapses. To address my hypothesis, I will exclusively use human dorsal root ganglia from organ donors. Aim 1 will use bioinformatics to thoroughly characterize VGSC and modulator expression in human nociceptors. Aim 2 will employ patch-clamp electrophysiology to characterize tetrodotoxin (TTX)-resistant and -sensitive resurgent currents in human nociceptors. Aim 3 will model sensitization dependent voltage-gated sodium channel binding to modulators and examine sensitization-specific isoforms. This work will elucidate how unique expression patterns of VGSCs and their modulating proteins contribute to nociceptor sodium current, which is essential for understanding human nociception. This training opportunity will leverage advanced training in human molecular neuroscience that can only be done in a few labs in the world, guided by experts in sequencing technologies, electrophysiology and bioinformatics, and will prepare me for an independent academic career.
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