Understanding the Multiscale Mechanics of Nerve Endings to Address Visceral Pain

了解神经末梢的多尺度机制以解决内脏疼痛

• 批准号: 1727185
• 负责人: Bin Feng
• 金额: $ 43.25万
• 依托单位: University of Connecticut
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1727185&HistoricalAwards=false
• 关键词: Understanding; Multiscale; Mechanics; Nerve; Endings

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.

与肠易激综合征相关的内脏疼痛困扰着13%的美国人口，每年造成约300亿美元的损失。中空内脏器官的机械扩张会引起内脏疼痛。内脏痛药物通过相似的细胞感觉通路影响周围和中枢神经系统(CNS)。以这种方式治疗的患者会出现与大脑和脊神经相关的副作用，其中，身体依赖和成瘾尤其重要。器官机械扩张引起的内脏疼痛始于外周，靶向生物力学负荷的受体可以减少脑和脊柱的副作用。本项目旨在了解内脏神经的生物力学与慢性内脏疼痛的关系。这项研究将揭示特定于内脏器官的神经末梢-组织复合体的新治疗靶点，将中枢神经系统副作用降至最低，并改善慢性内脏疼痛患者的健康和生活质量。该项目将通过综合宣传，吸引代表人数不足的群体的学生，特别是妇女，在初中、高中和大学学习。PI和Co-Pi实验室的研究将与丹伯里图书馆和康涅狄格州大学的推广和多样性计划相结合，以吸引来自初中、高中和大学中代表性不足群体的学生，特别是女性。该项目的总体目标是了解对照(健康)和TNBS治疗(疼痛)结直肠癌中结肠组织的多尺度生物力学和感觉神经末梢周围的微观机械环境。该中心假设，控制内脏机械感觉和敏化的因素包括：1)不同层次的大肠组织(如粘膜、肌肉)的力学性质不同；2)神经末梢与其细胞外基质之间偶联的不同微观力学；以及3)大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处理的结肠直肠)。这项工作旨在通过多尺度建模和模拟来确定：1)对照组(健康)和TNBS处理组(疼痛)小鼠结肠粘膜和肌层的组织水平生物力学；2)对照组和TNBS处理组小鼠单个结直肠感觉神经末梢的微观力学环境；3)神经末梢应力/应变对内脏神经机械感觉和敏化功能异质性的影响。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。这项研究将引入以前被忽视的生物力学作为内脏伤害和疼痛的关键因素，建立新的生物力学工具，并扩大目前关于内脏机械感觉和疼痛的知识。

项目成果

Optical recording reveals topological distribution of functionally classified colorectal afferent neurons in intact lumbosacral DRG

• DOI: 10.14814/phy2.14097
• 发表时间: 2019-05-01
• 期刊: PHYSIOLOGICAL REPORTS
• 影响因子: 2.5
• 作者: Guo, Tiantian;Bian, Zichao;Feng, Bin
• 通讯作者: Feng, Bin

Differential biomechanical properties of mouse distal colon and rectum innervated by the splanchnic and pelvic afferents

• DOI: 10.1152/ajpgi.00324.2018
• 发表时间: 2019-04-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
• 影响因子: 4.5
• 作者: Siri, Saeed;Maier, Franz;Feng, Bin
• 通讯作者: Feng, Bin

Toward Elucidating the Physiological Impacts of Residual Stresses in the Colorectum

阐明结直肠残余应力的生理影响

• DOI: 10.1115/1.4051846
• 发表时间: 2022
• 期刊: Journal of Biomechanical Engineering
• 作者: Zhao, Y.;Siri, S.;Feng, B.;Pierce, D. M.
• 通讯作者: Pierce, D. M.