Disordered Tissue Biomechanics as a Driver of Esophageal Disease

项目总结 食道疾病非常常见，每年因吞咽困难而门诊就诊的患者超过100万人次，占20% 在患有胃食道反流病的人口中，约有50,000人 因食物嵌塞而接受内窥镜检查一年。症状集中在吞咽困难，胸痛， 反流和对窒息的恐惧极大地影响生活质量，而吸入和营养不良是相关的 而且死亡率很高。中枢性食道疾病的发病机制是团剂运输异常，这 功能依赖于微妙的机械相互作用，因为食道必须容纳很大的容量 在短时间内，并在低压状态下推动推进剂进入食道。考虑到这种微妙的平衡， 即使是食管壁膨胀性的微小变化也会对丸剂的运输和 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，因为大部分的重点一直是蠕动和收缩的活力。vbl.使用 我们实验室开发的专注于高分辨率阻抗的新技术，我们的团队已经能够展示 食管壁的机械性能和对容量扩张的反应在 食道疾病的发病机制。使用功能性管腔成像探头(Flip)并改进这项技术 在翻转容积法中，我们能够确定定义嗜酸性粒细胞管壁扩张性的新指标 食管炎、失弛缓症和非梗阻性吞咽困难。此外，我们还定义了一种新的运动模式 由扩张直接刺激的，可能代表重复形式的二次蠕动样反应 顺行性收缩(RAC)。进一步的工作集中在RAC的支持上，即这种响应具有重要的意义 吞咽困难患者食管酸清除和团注转运的功能和临床相关性。鉴于此， 初步数据，我们已经制定了一项计划项目赠款(PPG)，重点是“混乱的组织 生物力学是食道疾病的驱动因素“。为了充分了解这一致病机制， 我们汇集了一组具有不同专业知识的调查人员，以开发一个全面的模型 疾病活动使用四管齐下的攻击。项目1将确定背后的触发因素和分子机制 食管壁异常扩张性和项目2将研究食管壁扩张性在改变食管壁膨胀性中的作用 对体积膨胀的反应主要集中在其对团注运输的影响上。项目3将利用直接措施 来自项目2的组织材料特性和生理数据，以开发食道的硅胶模型 传输以测试在项目1和2中得出的假设和反向工程混合诊断 可以确定翻转和测压发现的异常功能背后的实际力学。最后的, 项目4将确定中央调节的认知过程在症状上的作用，并作为一个总体 目标开发一个复杂的模型，它将包括生理生物标记物、机械性能的测量 食管壁与产生症状的心理介质有关。

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.