Visceral pain associated with irritable bowel syndrome afflicts 13% of the US population, costing approximately $30 billion annually. Mechanical distension of hollow visceral organs evokes visceral pain. Drugs for visceral pain affect both peripheral and central nervous systems (CNS) due to similar cellular sensory pathways. Patients treated in this way suffer brain and spinal nerve related side effects, and among those, physical dependency and addiction are particularly important. Visceral pain by mechanical distension of organs initiates in the periphery, making it possible that targeting the receptors of biomechanical loading could reduce the brain and spine side effects. This project aims to understand the biomechanics of visceral nerves as relates to chronic visceral pain. This research will reveal novel therapeutic targets in the nerve ending-tissue complex specific to visceral organs, minimizing CNS side effects and improving health and quality of life for patients suffering chronic visceral pain. This project will engage students from underrepresented groups, particularly women, in middle school, high school and university through integrated outreach. Research in the PI's and Co-PI's labs will be integrated with outreach and diversity programs at the Danbury Library and UConn to engage students from underrepresented groups, particularly women, in middle school, high school and university.
The overall objective of this project is to understand the multiscale biomechanics of colorectal tissue and the micromechanical environment surrounding sensory nerve endings in both control (healthy) and TNBS-treated (in pain) colorectums. The central hypothesis posits that factors governing visceral mechanosensation and sensitization include: 1) varying mechanical properties across different layers of colorectal tissue (e.g. mucosal, muscular), 2) distinct micromechanics at couplings between nerve endings and their extracellular matrix, and 3) dynamic changes in tissue biomechanics following colorectal tissue damage and nerve ending regeneration (in TNBS-treated colorectum). This work aims to determine: 1) tissue-level biomechanics of mucosal and muscular layers of colorectum from both control (healthy) and TNBS-treated (in pain) mice, 2) micro-mechanical environments of individual colorectal sensory nerve endings from both control and TNBS-treated mice, and 3) the impact of nerve ending stress/strain on functional heterogeneity of visceral neural mechanosensation and sensitization via multiscale modeling and simulation. This project leverages novel approaches, including: a mouse IBS model of pain produced by trinitrobenzene sulfonic acid (TNBS), genetic sensory nerve labeling, optical tissue clearing, and multiscale modeling of mechanosensation together with nonlinear soft tissue biomechanics and imaging of collagen fibers. This research will introduce previously overlooked biomechanics as a critical factor in visceral nociception and pain, establish novel biomechanical tools and expand current knowledge of visceral mechanosensation and pain.
