Project Summary There is vast inter-individual variability to acute and chronic pain, and genetic architecture is one of the major factors that shape our unique responses to pain. The misexpression of genes in nociceptors can facilitate the transition from acute to chronic pain, and thus targeting nociceptor genes in the periphery is an important route towards non-addictive pain therapeutics. If we seek to uncover how diverse human genomes may give rise to pathological pain sensation, a narrow focus in our preclinical studies on one canonical wildtype mouse line, C57BL/6J, is insufficient. Moreover, to harness the full translational potential of mouse models of pain, a prerequisite is being able to accurately measure pain, which is an inherently subjective sensation that becomes even harder to score in nonverbal animals. In recent publications from my lab, we have developed automated mouse “pain scales” using high-speed videography, machine learning, and custom software, to capture the sensory-reflexive dimensions of pain in a quantitative manner. In ongoing studies, we use unsupervised learning platforms to automatically capture spontaneous signatures of pain. Therefore, we are now well-positioned to use our automated pain behavior assessment platforms to test new pain target genes and identify genetically divergent mice with atypical pain sensitivity. We have three major goals in this New Innovator Award program. First, we aim to identify genetically unique mouse lines that have unusual responses to acute and chronic pain, using evoked and spontaneous pain measurements, testing hundreds of mice. The mouse lines tested in this application that fail to respond normally to pain, or have heightened pain responses, may hold the keys to uncovering how populations of people have pathological pain sensitivity. This is significant because individuals with hypersensitivity to pain, appear to have an increased risk of developing chronic pain. The genetic construction of these mouse lines also facilitates mapping analyses to connect genes to pain traits, thus identifying potential new pain targets. Second, we will investigate the biological basis of pain sensitivity in a mouse line that my lab already published on, as having mechanical pain hypersensitivity. We aim to identify causative changes that permit this hypersensitivity, and thus unlock a new pain target. Finally, we will use mouse genetic targeting to ablate a candidate pain target in mouse nociceptors and test functional consequences with our automated behavioral pipelines. This new candidate gene recently emerged from single-cell RNA sequencing of human nociceptors. Taken together, we are levering the tools my lab developed and resources made available to the entire community, to produce an atlas of pain hyper- and hypo-sensitive mouse lines, as well as functionally identifying new pain therapeutic targets.

Project Narrative The proposed research is relevant to public health because it will identify genetically diverse mouse lines with heightened or reduced pain sensitivity that can be used for finding new targets to treat chronic pain. In this project we will also seek to identify new pain targets which come directly from studies sequencing pain neurons in humans. The project is relevant to the mission of NIH because of its potential to mirror the genetic diversity to pain sensation observed in humans – in preclinical mouse models, thus enhancing our fundamental understanding of the role of genetics in pain sensation.