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NIH grant 1RF1NS141359-01A1: Human Chemo-Nociceptor Signaling
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Steve Davidson. Award: $3851810.
Start: 2026-09-12T00:00:00.
PROJECT SUMMARY
Chronic pain is an enormous and urgent health burden in the United States on a growth trajectory. Safe and
effective alternative pain medicines to replace dangerous, ineffective, or addictive current treatments (such as
opioids) have shown unsatisfactory clinical translation from animal models. We have developed methods to
recover viable peripheral nervous system including the pain and itch signaling neurons from the dorsal root
ganglia (DRG) from human cadaveric organ donors. These gifted, viable tissues provide unique opportunities
to obtain high-validity human preclinical data on the physiologic, molecular, genetic, and cell signaling
mechanisms that contribute to chronic pain. Recently, we showed that human nociceptors exhibit important
genetic differences compared to rodent models that can impact clinical outcomes. In this project, we will
leverage human donor tissue recovery to facilitate target identification, drug discovery, and the development of
novel medicines to treat pain and itch. In Aim 1 we generate the first protein expression atlas of the human
DRG at cellular resolution which will provide a comprehensive guide for drug targets. This highly multiplexed
catalog of protein expression is possible with our innovative approach of imaging mass cytometry. The results
will test the hypothesis that gene expression alone does not accurately predict protein expression, and we
expect the proteomic data will challenge the current RNA-based characterization of sensory neuron subtypes.
Next, in Aim 2 we investigate the physiology and intracellular signaling of the human chemo-sensitive
nociceptors, focusing on the human-specific MRGPRX class of transmembrane receptors thought to be critical
for pruriception, nociception, and inflammation. These human-specific G-protein coupled receptors are not
expressed in rodents, and their molecular signaling pathways and functional roles in pain and itch in native
human nociceptors are unknown. In Aim 3 we examine communication between human chemo-sensory
neurons and human keratinocyte skin cells using a novel all-human co-culture microfluidic model. We
determine how innervated end-organ skin cells exert control on sensory neuron identity, morphology, and
physiology. We have developed a well-controlled ultraviolet radiation injury that will be used to investigate
human nociceptors to understand how burn injury affects neural sensitization, innervation plasticity, and skin
regeneration. Together these aims will build the foundation for human-based preclinical research on pain and
itch and develop new models that de-risk efforts for drug discovery and therapeutic development.document fetched 2026-09-20 02:42