Disordered Tissue Biomechanics as a Driver of Esophageal Disease

项目摘要 食管疾病非常常见，每年有超过100万例吞咽困难门诊就诊，20% 的胃食管反流病患者和约50，000名急诊患者， 因为食物嵌塞而进行的内窥镜检查症状主要是吞咽困难，胸痛， 反胃和对窒息的恐惧严重影响生活质量， 死亡率很高食管疾病发病机制的中心是异常的食团转运， 功能依赖于微妙的机械相互作用 并在低压状态下沿食道向下推进食团。鉴于这种微妙的平衡， 即使食管壁扩张性的微小变化也会对食团输送产生显著影响， 食管壁的应变/应力关系。到目前为止，对这些问题的调查很少。 重要的机械过程，因为大多数的重点一直在收缩和收缩活力。使用 我们实验室开发的新技术专注于高分辨率阻抗，我们的团队已经能够证明 食管壁的机械特性和对容积扩张的反应在 食管病病机使用功能性管腔成像探头（FLIP）并改进该技术 在FLIP-全景测量中，我们能够确定定义嗜酸性粒细胞性室壁扩张性的新指标， 食管炎、贲门失弛缓症和非阻塞性吞咽困难。此外，我们定义了一种新的运动模式， 由扩张直接刺激，并可能代表重复性蠕动形式的次级蠕动样反应。 顺行性收缩（RAC）。进一步的工作侧重于相关活动协调员的支持，即这一应对措施具有重要意义 功能和临床相关性的食管酸清除和丸剂运输吞咽困难。鉴于这种 初步数据，我们已经制定了一个计划项目赠款（PPG）的重点是“无序组织 生物力学作为食管疾病的驱动因素。为了充分了解这种致病机制， 我们召集了一组具有不同专业知识的调查人员， 使用四管齐下的攻击进行疾病活动。项目1将确定背后的触发器和分子机制 项目2将研究食管壁扩张性对改变食管壁扩张性的影响。 对体积扩张的反应集中在其对团注运输的影响上。项目3将采用直接措施 项目2的组织材料特性和生理数据，以开发食管的计算机模拟模型 运输，以测试项目1和2中得出的假设，并对混合诊断进行逆向工程， 可以确定FLIP和测压法发现的异常功能背后的实际机制。最后， 项目4将确定中央介导的认知过程对症状的作用，并作为一个总体的 目标开发一个复杂的模型，将纳入生理生物标志物，机械性能的措施， 食管壁与症状产生的心理介质。

PROJECT SUMMARY Esophageal diseases are extremely common with over a million outpatient clinic visits for dysphagia a year, 20% of the population suffering with gastroesophageal reflux disease and approximately 50,000 emergent endoscopies being performed a year for food impactions. Symptoms focused on dysphagia, chest pain, regurgitation and fear of choking dramatically impact quality of life and aspiration and malnutrition are associated with significant mortality. Central to esophageal disease pathogenesis is abnormal bolus transport and this function is dependent on a delicate mechanical interplay as the esophagus must accommodate a large volume in a short time and propel the bolus down the esophagus in a low-pressure state. Given this delicate balance, even small changes in esophageal wall distensibility can have dramatic effects on bolus transport and the strain/stress relationship of the esophageal wall. To date, there has been very little investigation into these important mechanical processes as most of the emphasis has been on peristalsis and contractile vigor. Using novel techniques developed in our lab focused on high-resolution impedance, our team has been able to show that the mechanical properties of the esophageal wall and the response to volume distention are important in esophageal disease pathogenesis. Using the functional lumen imaging probe (FLIP) and refining this technique into FLIP-panometry, we were able to determine new metrics that define wall distensibility in eosinophilic esophagitis, achalasia and non-obstructive dysphagia. Additionally, we defined a new motor pattern that was directly stimulated by distention and likely represents a secondary peristaltic like response in the form of repetitive antegrade contractions (RACs). Further work focused on RACs support that this response has important functional and clinical relevance in esophageal acid clearance and bolus transport in dysphagia. Given this preliminary data, we have developed a program project grant (PPG) focused on “Disordered Tissue Biomechanics as a Driver of Esophageal Diseases”. In order to fully understand this pathogenic mechanism, we have brought together a group of investigators with varying expertise to develop a comprehensive model of disease activity using a 4 pronged attack. Project 1 will determine the triggers and molecular mechanisms behind abnormal wall distensibility and Project 2 will study the effect of esophageal wall distensibility on altering the response to volumetric distention focused on its effect on bolus transport. Project 3 will utilize direct measures of tissue material properties and physiologic data from Project 2 to develop in-silico models of esophageal transport to both test the hypotheses derived in Projects 1 and 2 and reverse engineer hybrid diagnostics that can determine the actual mechanics behind the abnormal function uncovered by FLIP and manometry. Last, Project 4 will determine the role of central mediated cognitive processes on symptoms and as an overarching goal develop a complex model that will incorporate physiologic biomarkers, measures of mechanical properties of the esophageal wall with psychological mediators of symptom generation.