The Esophagogastric Junction in Health and Disease

描述(申请人提供)：胃食道反流病(GERD)是最常见的食道疾病，5%-7%的美国成年人每天都会经历最常见的症状(烧心)。GERD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，PPI不能治愈GERD，GERD是一种没有公认的胃酸分泌异常的疾病。相反，通过将胃酸分泌减少到异常低的水平，PPI可以部分补偿GERD的生理异常。从生理上讲，GERD的特征是食管胃交界处(EGJ)功能不全，胃分泌物过度反流进入食道。反流过多的影响因反流产物的食道清除不良而加重。本研究项目的基本目标是将GERD发病机制的思维范式从下食道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，即发病的早期阶段。该应用程序代表了胃肠病学家(Kahrilas博士和Pandolfino博士)以及对胃肠道生理学长期感兴趣的机械工程师(Brasseur博士和Ghosh博士)的合作努力。研究方法包括高分辨率固态测压、腔内置入和同步透视、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，以便于模拟影响EGJ的解剖和生理变量之间的复杂相互作用。研究的主要生理特性是EGJ的轴向流动性和顺应性。据推测，两者的异常可能是由于腹部肥胖和与年龄相关的变化造成的慢性机械压力，最终破坏了EGJ的功能。建立有效的GERD治疗的生理学标准是本研究项目的一个根本目标。这个研究小组的未来方向将是设计和测试基于这些生理目标的“矫正干预”。

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.