MECHANISMS OF ACID RESISTANCE IN BARRETT'S ESOPHAGUS

巴雷特食管的抗酸机制

基本信息

批准号：
6665298
负责人：
Roy Charles Orlando
金额：
$ 28.35万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2007-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Barrett's esophagus denotes the presence of specialized columnar epithelium (SCE) in distal esophagus. It develops in subjects with acid reflux disease as replacement for destroyed esophageal stratified squamous epithelium (ESSE). In 90%, it remains stable for life and irrespective of treatment since most - presumably because of its acid resistance - are (reflux) symptom-free. In one sense, then, Barrett's is a successful adaptation for esophageal protection. Barrett's, however, has a high cell turnover rate which establishes it as a premalignant lesion that increases esophageal cancer risk 40-fold over the general population. Though clinically important, little is known about the biology of SCE, and specifically about the mechanisms for acid resistance that are at the heart of its very existence. Therefore the goals of this proposal are: a) to define the preepithelial and epithelial mechanisms for SCE's survival under acidic stress: b) compare them to ESSE in Barrett's in order to test the hypothesis that SCE develops in GERD because of intrinsic mechanisms that make it more acid resistant than ESSE, and c) since alcohol and cigarette smoking increase the risk of malignancy in SCE, test the hypothesis that this risk reflects the ability of these agents to shorten cell survival I (which increases cell turnover) by impairing SCE's ability to protect itself under an acidic stress. The specific aims are to determine in SCE and ESSE in Barrett s: 1) the magnitude of the lumen-to-surface pH gradient and role of mucus and HCO3, 2) the permeability of the apical membrane-junctional complex to H+, 3) the total cell buffer capacity and role of carbonic anhydrase, 4) the nature, location and activity of transporters for pHi regulation, 5) the effect of alcohol and smoking on cell survival under an acid stress, and to: 6) compare the results to ESSE in those without esophageal disease. Studies are performed using esophageal biopsies for cell isolation, culture and mounting in mini-Ussing chambers. Techniques include: pH icroelectrodes, immunohistochemistry, impedance analysis and fluorescence microscopy. Achievement of the proposed goals will yield information of fundamental importance to understanding the pathogenesis and malignant potential of SCE in reflux subjects and provide insights into possible novel strategies for its prevention, stabilization or selective eradication for reduction of cancer risk.

描述（由申请人提供）：巴雷特的食管表示在远端食管中存在专门的柱状上皮（SCE）。它在患有胃酸反流疾病的受试者中发展为替代了破坏的食管分层鳞状上皮（ESSE）。在90％的人中，它的生命仍然稳定，无论治疗如何，因为大概是由于其抗酸性 - 反流）症状。从某种意义上说，巴雷特的成功改编了食管保护。然而，巴雷特的细胞更新率很高，它将其确定为前病变，可将食管癌风险增加40倍以比普通人群的风险增加。尽管在临床上很重要，但对SCE的生物学知之甚少，尤其是关于其存在核心的抗酸性机制。 Therefore the goals of this proposal are: a) to define the preepithelial and epithelial mechanisms for SCE's survival under acidic stress: b) compare them to ESSE in Barrett's in order to test the hypothesis that SCE develops in GERD because of intrinsic mechanisms that make it more acid resistant than ESSE, and c) since alcohol and cigarette smoking increase the risk of malignancy in SCE, test the hypothesis that this risk reflects这些药物通过损害SCE在酸性应激下保护自身的能力来缩短细胞存活I（增加细胞周转）的能力。 The specific aims are to determine in SCE and ESSE in Barrett s: 1) the magnitude of the lumen-to-surface pH gradient and role of mucus and HCO3, 2) the permeability of the apical membrane-junctional complex to H+, 3) the total cell buffer capacity and role of carbonic anhydrase, 4) the nature, location and activity of transporters for pHi regulation, 5) the effect of alcohol and smoking on cell survival在酸应激下，至：6）将结果与没有食管疾病的患者进行比较。使用食道活检进行研究，以在小动物室中进行细胞分离，培养和安装。技术包括：pH ICRECTRODES，免疫组织化学，阻抗分析和荧光显微镜。实现拟议的目标将产生基本重要性的信息，以理解SCE在反流体受试者中的发病机理和恶性潜力，并为预防，稳定或选择性消除癌症风险提供新的新型策略。