Hedgehog in Barrett's esophagus & assoc. adenocarcinoma

巴雷特食道里的刺猬

• 批准号: 7474743
• 负责人: DAVID H WANG
• 金额: $ 5.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-26 至 2009-07-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474743
• 关键词: Adenocarcinoma; Adult; American; Barrett Esophagus; Bile Acids; Bile Reflux; Cancer Etiology; Cessation of life; Chemopreventive Agent; Clinical; Condition; Country; Data; Development; Distal; Dysplasia; Epithelial; Epithelium; Erinaceidae; Esophageal; Esophageal Adenocarcinoma; Esophagectomy; Esophagitis; Esophagus; Event; Gastric Acid; Heartburn; Injury; Invasive; Lead; Ligands; Link; Malignant neoplasm of esophagus; Mediating; Medical Surveillance; Metaplasia; Mutation; Pathogenesis; Pathway interactions; Patients; Population; Pre-Clinical Model; Primitive foregut structure; Proton Pump Inhibitors; Reflux; Risk; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Translating; Up-Regulation; base; inhibitor/antagonist; men; prevent; smoothened signaling pathway; transdifferentiation

DESCRIPTION (provided by applicant): Esophageal cancer is the sixth leading cause of cancer death worldwide and in American men. Adenocarcinoma, the prevalent type in the US, arises from Barrett's esophagus, a metaplastic change in the distal esophagus. Unfortunately, an understanding of signaling pathways that link the initiation of metaplasia to development of adenocarcinoma is lacking. Based on preliminary data, we hypothesize that aberrant Hedgehog pathway activation, necessary for normal foregut development, is a critical early event in the development of Barrett's metaplasia and continues in the progression to adenocarcinoma. With this proposal, we hope to determine if (1) Hedgehog pathway activation is a cause of Barrett's metaplasia, (2) acid and bile reflux can activate the Hedgehog pathway, (3) p63 is a downstream target of Hedgehog signaling which mediates epithelial transdifferentiation and (4) Hedgehog pathway specific inhibitors can prevent and/or treat esophageal adenocarcinoma in preclinical models. The long-term clinical objective of these studies is translating Hedgehog pathway inhibitors into a chemopreventive therapy for Barrett's esophagus and a targeted therapy for invasive adenocarcinoma.

描述（由申请人提供）：食管癌是全球癌症死亡和美国男性的第六个主要原因。腺癌是美国的普遍类型，是由巴雷特的食管腺癌（远端食道的化生变化）引起的。不幸的是，缺乏对将化合物开始与腺癌发展联系起来的信号通路的理解。基于初步数据，我们假设对正常发育所必需的异常刺猬途径激活是Barrett Metaplasia发展的关键早期事件，并且持续发展为腺癌。有了该建议，我们希望确定（1）刺猬途径的激活是否是巴雷特元素的原因，（2）（2）酸和胆汁反流可以激活刺猬途径，（3）p63是刺猬信号的下游靶标，可以介导上皮的转移和（4）特定于/治疗特定于/（4）怪异的怪异途径，以刺激途径。临床前模型中的腺癌。这些研究的长期临床目标是将刺猬途径抑制剂转化为Barrett食管的化学预防疗法，并将其针对侵入性腺癌的靶向疗法转化为化学疗法。