Understanding the Multiscale Mechanics of Nerve Endings to Address Visceral Pain

与肠易激综合征相关的内脏疼痛折磨着13%的美国人，每年花费约300亿美元。空心内脏器官的机械膨胀引起内脏疼痛。由于类似的细胞感觉通路，治疗内脏疼痛的药物同时影响外周和中枢神经系统。以这种方式治疗的患者会遭受与大脑和脊神经相关的副作用，其中，身体依赖和成瘾尤为重要。由器官机械膨胀引起的内脏疼痛始于外周，这使得靶向生物力学负荷受体可能减少脑和脊柱的副作用。本项目旨在了解与慢性内脏疼痛有关的内脏神经的生物力学。本研究将揭示内脏器官特异性神经末梢组织复合物的新治疗靶点，最大限度地减少中枢神经系统的副作用，改善慢性内脏疼痛患者的健康和生活质量。该项目将通过综合外展吸引初高中和大学中代表性不足群体的学生，特别是妇女。PI和Co-PI实验室的研究将与丹伯里图书馆和康涅狄格大学的外展和多元化项目相结合，以吸引初高中和大学中代表性不足群体的学生，尤其是女性。本项目的总体目标是了解对照组（健康）和tnbs治疗组（疼痛）结直肠组织的多尺度生物力学和感觉神经末梢周围的微力学环境。核心假设认为，控制内脏机械感觉和致敏的因素包括：1)不同层次结直肠组织（如粘膜、肌肉）的不同力学特性，2)神经末梢与其细胞外基质耦合的不同微观力学，以及3)结直肠组织损伤和神经末梢再生后组织生物力学的动态变化（在tnbs治疗的结直肠中）。本研究旨在通过多尺度建模和模拟确定：1)对照组（健康）和tnbs治疗小鼠（疼痛）结直肠粘膜和肌肉层的组织水平生物力学，2)对照组和tnbs治疗小鼠个体结直肠感觉神经末梢的微力学环境，以及3)神经末梢应激/应变对内脏神经机械感觉和致敏功能异质性的影响。该项目利用了新的方法，包括：三硝基苯磺酸（TNBS）产生的小鼠IBS疼痛模型，遗传感觉神经标记，光学组织清除，机械感觉的多尺度建模以及非线性软组织生物力学和胶原纤维成像。本研究将引入以前被忽视的生物力学作为内脏痛觉和疼痛的关键因素，建立新的生物力学工具，并扩展目前对内脏机械感觉和疼痛的认识。

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.