Mapping Stromal Contributions to Chronic Pain: Building a Cross-Species Atlas to Reveal Stromal Cells Impact in Pain Aetiology

Abstract
Chronic pain, often arising in the context of inflammatory disorders across mammalian species, constitutes a pervasive and complex physiological condition that affects the functionality and wellbeing of organisms. While acute pain serves a vital protective function, prompting immediate responses to harmful stimuli, chronic pain represents a maladaptive state as it persists beyond the resolution of the initial injury or inflammation. Recent findings suggest that chronic pain can be decoupled from inflammation, with stromal cells emerging as key contributors to this phenomenon. Despite significant advancements in understanding pain mechanisms, a comprehensive elucidation of the genetic and molecular pathways underpinning chronic pain - specifically, those involving stromal cells - remains elusive. The advent of high-throughput sequencing and single-cell technologies has revolutionised our ability to investigate gene expression and regulation with unprecedented granularity, providing a wealth of data for unravelling the intricate molecular mechanisms underlying chronic pain. However, the effective integration and analysis of these diverse and high-dimensional datasets to extract biologically meaningful insights pose a significant challenge. This study introduces a cutting-edge framework that integrates multi-omics datasets from tissues with high stromal cell composition linked to chronic pain conditions. By leveraging single-cell technologies and probabilistic machine learning models, we aim to identify novel non-neuronal pain-associated genes, validate gene modules associated with chronic pain identified in previous studies and elucidate the roles of stromal cells in pain. Furthermore, we investigate the variability and conservation of pain responses across species, providing a comprehensive understanding of chronic pain aetiology. This integrative analysis paves the way for the development of a standardised molecular definition of pain, the discovery of potential therapeutic targets, and a deeper understanding of pain perception at the cellular level, ultimately transforming our understanding of chronic pain and informing the development of more effective therapeutic interventions.
BBSRC Priority Areas: Animal health, Data-driven biology, Systems approaches to the biosciences, Technology development for the biosciences, e-Science, Lifelong Health and Wellbeing, Bioscience for an integrated understanding of health, understanding the rules of life.