Defining and modeling the cellular interactions for rhythmic colon motility

节律性结肠运动的细胞相互作用的定义和建模

• 批准号: 10711530
• 负责人: Kristen Michelle Smith-Edwards
• 金额: $ 52.64万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711530
• 关键词: Address; Affect; Afferent Neurons; Anus; Behavior; Calcium; Cell Communication; Cell model; Cells; Colon; Colonic Diseases; Colonic inflammation; Complex; Computer Models; Coupled; Data; Devices; Distal; Ensure; Enteric Nervous System; Frequencies; Functional disorder; Gastrointestinal Motility; Goals; Health; Human; Image; Immunofluorescence Immunologic; In Situ; Individual; Inflammation; Interstitial Cell of Cajal; Knowledge; Length; Measures; Mechanics; Migrating Myoelectric Complex; Modeling; Motor; Motor Neurons; Movement; Mus; Muscle Tonus; Nerve; Neuromechanics; Neurons; Oral; Organ; Organism; Pacemakers; Pattern; Periodicity; Property; Relaxation; Research Personnel; Smooth Muscle; Stimulus; Stretching; Symptoms; System; Technology; Testing; Therapeutic; Work; absorption; cell motility; cell type; effective therapy; imaging approach; in silico; motility disorder; neural; neurochemistry; neuroregulation; novel; novel therapeutics; optogenetics; programs; restoration; sensory input; wasting

ABSTRACT: Continuous colon motility is critical for the overall health and survival of an organism and results from activity in the enteric nervous system (ENS) and interstitial cells of Cajal (ICC) that are electrically-coupled to smooth muscle. Although these cellular components have been individually studied in detail, how they interact to coordinate motility across the length of colon is not well understood. Two motor patterns are measured experimentally: (1) ‘ripple’ contractions produced by ICC slow waves of depolarization, and (2) colon migrating motor complexes necessary for propulsion of fecal contents that require ENS activity. Existing models of colon motility are focused on distal regions where distension from a fecal pellet activates intrinsic sensory neurons (or IPANs) that excite ENS motor neurons for oral contraction and anal relaxation of smooth muscles; the forward movement of the pellet then distends the adjacent segment, activates another IPAN, and this ‘neuromechanical loop’ ensures propagation and propulsion of fecal contents. However, these models do not explain the regular rhythm of colon motor complexes, which occur every 2-5 min, or how they are first initiated in the proximal colon where fecal pellets have not yet formed. Unlike motor complexes that reach distal regions only when sensory input is applied, spontaneous, rhythmic motor complexes occur in proximal regions regardless of luminal content, stretch, or distension, indicating that the proximal colon has unique pacemaker capabilities that determine the rhythm of motor complexes. The objective for this project is to determine and model the cellular interactions unique to the proximal colon that are responsible for generating rhythmic motor complexes in normal and inflamed conditions. We hypothesize that rhythmic motor complexes are due to cyclical interactions among ICC, IPANs and motor neurons of the ENS, and that dysmotility during inflammation is due to dysregulation of these interactions. To test this and address knowledge gaps, we will use optogenetics, calcium imaging, in situ immunofluorescence, and computational modeling to define the cell-to-cell interactions responsible for spontaneous, rhythmic motor complexes produced in the proximal colon and determine the cellular components that contribute to dysrhythmic motility following inflammation. Aim 1 will determine the mechanical sensitivity of proximal colon IPANs to ICC-generated ripple contractions. Aim 2 will define the ‘ENS neural program’ activated by IPANs that produces motor complexes in proximal colon. Aim 3 will determine the effect of ENS activity on ICC slow waves and ripple contractions. Each Aim will collect data from normal and inflamed colons, and findings will be incorporated into our model to computationally test whether predictions can be made regarding motility behavior based on changes in cellular activity. Thus, these studies will yield a novel computational model that will help identify cellular mechanisms of dysfunction in colon diseases and guide optimization of therapeutic devices that employ pacemaker technology or nerve stimulation to normalize and restore colon function.

摘要：持续的结肠运动对于有机体的整体健康和生存及其结果至关重要 来自电耦合的肠神经系统 (ENS) 和卡哈尔间质细胞 (ICC) 的活动 尽管这些细胞成分已被单独详细研究，但它们如何相互作用。 协调结肠长度的运动尚不清楚，测量了两种运动模式。 实验上：（1）ICC 去极化慢波产生的“波纹”收缩，以及（2）结肠迁移 推进需要 ENS 活动的粪便内容物所必需的运动复合体。 运动集中在远端区域，粪便颗粒的扩张激活了内在的感觉神经元（或 IPAN）刺激 ENS 运动神经元，使平滑肌进行口腔收缩和肛门松弛； 颗粒的运动会扩张相邻节段，激活另一个 IPAN，而这种“神经机械” “循环”确保了粪便内容物的传播和推进然而，这些模型并没有解释常规。 结肠运动复合体的节律，每 2-5 分钟发生一次，或者它们如何在近端结肠中首次启动 与仅在感觉时到达远端区域的运动复合体不同，粪便颗粒尚未形成。 应用输入，自发的、有节律的运动复合体发生在近端区域，无论管腔内容如何， 拉伸或扩张，表明近端结肠具有独特的起搏器功能，决定了 该项目的目标是确定和模拟细胞相互作用。 近端结肠所特有的，负责在正常和正常情况下产生节律性运动复合体 我们勇敢地说，节律性运动复合体是由于 ICC 之间的周期性相互作用造成的。 IPAN 和 ENS 运动神经元，炎症期间的运动障碍是由于这些神经元的失调造成的 为了测试这一点并解决知识差距，我们将使用光遗传学、钙成像、原位技术。 免疫荧光和计算模型来定义细胞间的相互作用 近端结肠产生自发的、有节律的运动复合体并确定细胞成分 导致炎症后运动失常的因素 目标 1 将决定机械敏感性。 近端结肠 IPAN 与 ICC 产生的波纹收缩的目标 2 将定义激活的“ENS 神经程序”。 目的 3 将确定 ENS 活性对近端结肠产生运动复合体的影响。 ICC 慢波和波纹收缩将收集正常结肠和发炎结肠的数据以及结果。 将被纳入我们的模型中，以计算测试是否可以对运动性做出预测 因此，这些研究将产生一种新的计算模型，该模型可以基于细胞活动的变化。 将有助于确定结肠疾病功能障碍的细胞机制并指导优化治疗 采用起搏器技术或神经刺激来使结肠功能正常化和恢复的设备。