The Esophagogastric Junction in Health and Disease

描述（由申请人提供）：胃食管反流病（GERD）是最常见的食道疾病，5-7%的美国成年人每天都会经历其最常见的症状（胃灼热）。胃食管反流往往是一种慢性疾病，是质子泵抑制剂（PPI）药物销售的主要适应症，2004年在美国的销售额超过140亿美元。然而，PPIs并不能治愈胃反流，这是一种没有胃酸分泌异常的疾病。相反，通过减少胃酸分泌到异常低的水平，ppi部分补偿了胃反流的生理异常。生理上，胃食管反流的特征是食管胃交界（EGJ）功能不全，胃分泌物过度反流至食管。过度反流的影响由于食管对反流的清除不良而加剧。本研究项目的基本目标是改变关于胃食管反流病发病机制的思维范式，从食管下括约肌功能本身转向调节括约肌功能并最终导致功能障碍的解剖和生理因素；发病的早期阶段。这一应用代表了胃肠病学家（Kahrilas博士和Pandolfino博士）和长期对胃肠生理学感兴趣的机械工程师（Brasseur博士和Ghosh博士）的合作成果。研究方法包括高分辨率固态测压法与腔内放置并与荧光透视同步，高分辨率腔内阻抗监测，腔内pH监测和高频腔内超声。由于EGJ括约肌功能的复杂性，将使用“计算机实验室”来开发EGJ的数学模型。建模将基于我们的实验数据，以方便模拟影响EGJ的解剖和生理变量之间复杂的相互作用。研究的关键生理特性是EGJ的轴向移动性和顺应性。据推测，这两种异常可能是由于腹部肥胖和年龄相关变化造成的慢性机械应力，最终破坏EGJ功能。建立有效的胃反流治疗的生理标准是本研究项目的基本目标。该研究小组未来的方向将是设计和测试基于这些生理目标的“纠正干预”。

DESCRIPTION (provided by applicant): Gastroesophageal reflux disease (GERD) is the most common disorder of the esophagus such that 5-7% of adult Americans experience its most common symptom (heartburn) on a daily basis. GERD tends to be a chronic disorder and is the leading indication for sales of proton pump inhibior (PPI) medications, amounting to more than $14 billion in the US in 2004. However, PPIs do not cure GERD, a condition with no recognized abnormality of gastric acid secretion. Rather, by reducing gastric acid secretion to abnormally low levels, PPIs partially compensate for the physiological abnormalities of GERD. Physiologically, GERD is characterized by incompetence of the esophagogastric junction (EGJ) with excessive reflux of gastric secretions into the esophagus. The impact of excessive reflux is compounded by poor esophageal clearance of that refluxate. The fundamental goal of this research project is to shift the paradigm of thought regarding GERD pathogenesis away from lower esophageal sphincter function per se and toward the anatomical and physiological factors that modulate sphincter function and ultimately lead to dysfunction; the earlier stages of pathogenesis. This application represents a collaborative effort by gastroenterologists (Dr Kahrilas and Dr Pandolfino), and mechanical engineers with long-standing interest in gastrointestinal physiology (Dr Brasseur and Dr Ghosh). Investigational methodologies include high-resolution solid-state manometry in conjunction with endoclip placement and synchronized with fluoroscopy, high resolution intraluminal impedance monitoring, intraluminal pH monitoring, and high frequency intraluminal ultrasound. Owing to the complexity of EGJ sphincteric function, a "computer laboratory" will be used to develop a mathematical model of the EGJ. Modelling will be based upon our experimental data to facilitate simulation of the complex interaction between anatomical and physiological variables affecting the EGJ. The key physiological properties targeted for investigation are the axial mobility and compliance of the EGJ. It is hypothesized that aberrations of both likely result from chronic mechanical stresses imposed by abdominal obesity and age- related change, ultimately undermining EGJ function. It is a fundamental goal of this research project to establish the physiological criteria for effective GERD therapy. A future direction for this research group will be to devise and test a "corrective intervention" based on those physiological objectives.