Disordered Tissue Biomechanics as a Driver of Esophageal Disease

组织生物力学紊乱是食管疾病的驱动因素

• 批准号: 10200791
• 负责人: JOHN E PANDOLFINO
• 金额: $ 144.81万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200791
• 关键词: Achalasia; Acids; Ambulatory Care Facilities; Animal Model; Architecture; Arousal; Atrophic; Biological Markers; Biology; Biomechanics; Bolus Infusion; Cell physiology; Chest Pain; Choking; Clinic Visits; Cognitive; Communities; Complex; Computer Simulation; Data; Deglutition; Deglutition Disorders; Development; Diagnostic; Discipline; Disease; Disease model; Endoscopy; Engineering; Enteral; Eosinophilic Esophagitis; Epithelial; Equilibrium; Esophageal Diseases; Esophagogastric Junction; Esophagus; Fibrosis; Food; Fright; Functional disorder; Gastroesophageal reflux disease; Generations; Goals; Heartburn; Histologic; Human; Hybrids; Hypersensitivity; Hypertrophy; Impairment; Injury; Intervention; Investigation; Link; Malnutrition; Manometry; Mathematical Model Simulation; Mathematics; Measures; Mechanics; Mediating; Mediator of activation protein; Minor; Modeling; Molecular; Morbidity - disease rate; Motor; Mucous Membrane; Muscle; Muscle Contraction; Muscular Atrophy; Neurons; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Peristalsis; Phenotype; Physiological; Physiology; Population; Process; Program Research Project Grants; Property; Psychometrics; Publications; Quality of life; Research; Research Personnel; Resistance; Resolution; Role; Scleroderma; Severities; Stimulus; Stress; Structure; Symptoms; System; Techniques; Testing; Time; Tissues; Visceral; Work; associated symptom; biomechanical engineering; cholinergic; clinically relevant; cognitive process; disease phenotype; electric impedance; flexibility; heart rate variability; imaging probe; improved; in silico; in vivo; mathematical model; mechanical properties; mortality; mouse model; novel; predict clinical outcome; pressure; psychologic; response; tool; virtual; virtual reality simulation

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.

项目摘要 食管疾病非常普遍，每年超过一百万个门诊诊所就诊，每年20％ 患有胃食管反应疾病的人口和大约50,000 内窥镜进行食物影响一年。症状着重于吞咽困难，胸痛， 反流和窒息的恐惧极大地影响生活质量，愿望和营养不良是相关的 死亡率很高。食管疾病发病机理的中心是推注的异常运输，这是 功能取决于精致的机械相互作用，因为食道必须容纳大量 在短时间内，将推注以低压状态下降。考虑到这种微妙的平衡， 即使食管壁的不良变化也可能对推注的运输和 食管壁的应变/应力关系。迄今为止，对这些的调查很少 重要的机械过程，因为大多数重点都放在蠕动和收缩活力上。使用 我们的团队在我们的实验室中开发的新技术专注于高分辨率阻抗，我们的团队能够展示 食管壁的机械性能和对体积距离的响应在 食管疾病发病机理。使用功能管腔成像探针（翻转）并完善此技术 进入翻转横幅学，我们能够确定定义嗜酸性粒细胞壁画的新指标 食管炎，adalasia和非刺激性吞咽困难。此外，我们定义了一种新的电机图案 直接通过延伸而刺激，可能代表重复形式的二次蠕动类似反应 步行收缩（RAC）。进一步的工作重点是RACS支持，这一反应具有重要 吞咽困难的食管酸清除和推注的功能和临床相关性。鉴于此 初步数据，我们已经开发了针对“无序组织的计划项目赠款（PPG） 生物力学是食管疾病的驱动力”。为了充分理解这种致病机制 我们汇集了一群具有不同专业知识的调查员，以开发一个全面的模型 疾病活性使用4支脚步攻击。项目1将确定触发因素和分子机制 异常的墙壁言语和项目2将研究食道壁的效果，可言语对改变 对体积扩张的反应集中在其对推注转运的影响。项目3将采用直接措施 来自项目2的组织材料特性和生理数据开发食管内硅内模型 运输以测试项目1和2中得出的假设，以及反向工程的混合诊断，这些假设 可以确定通过翻转和测量法发现的异常功能背后的实际力学。最后的， 项目4将确定中央介导的认知过程对症状的作用，而作为总体 目标开发一个复杂的模型，该模型将结合生理生物标志物，机械性能的度量 食管壁，具有症状产生的心理介体。