Hedgehog signaling in the development of Barrett's esophagus

巴雷特食管发育中的刺猬信号

基本信息

批准号：
9294054
负责人：
DAVID H WANG
金额：
$ 28.08万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9294054
关键词：
Acids Adult Affect American BMP4 Back Barrett Esophagus Bile fluid Biopsy Specimen Bone Morphogenetic Proteins CDX2 gene Cell Line Characteristics Clinical Trials Columnar Cell Columnar Metaplasia Country Cytokeratin Cytokeratin 8 Data Development Developmental Biology Disease Distal Drug Targeting Embryo Embryonic Development Endoscopic Biopsy Epithelial Epithelial Cells Epithelium Erinaceidae Esophageal Esophageal Adenocarcinoma Esophageal Squamous Cell Esophagitis Esophagus Fundoplication Gastric Acid Gastroesophageal reflux disease Gene Targeting Genes Goals Human In Vitro Incidence Intestines Lead Lesion Ligands Malignant Neoplasms Malignant neoplasm of esophagus Mesenchymal Metaplasia Molecular Molecular Target Morbidity - disease rate Mucous Membrane Mutation Pathway interactions Patients Pharmacology Phenotype Play Population Proteins Proton Pump Inhibitors Reflux Risk Role Signal Pathway Signal Transduction Squamous Epithelium Stomach Stratified Squamous Epithelium Telomerase Testing Therapeutic Therapeutic Agents Tissues Work bone morphogenetic protein 4 combinatorial design differential expression effective therapy experimental study in vivo inhibitor/antagonist innovation insight molecular marker molecular targeted therapies mortality new therapeutic target prevent public health relevance reactivation from latency response smoothened signaling pathway therapeutic target transcription factor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Barrett's esophagus, the metaplastic change of the distal esophageal epithelium from squamous to columnar, significantly increases the risk of esophageal adenocarcinoma, the prevalent form of esophageal cancer in this country. Understanding the molecular mechanism underlying esophageal epithelial columnar metaplasia is critical to designing molecularly targeted chemopreventative or therapeutic strategies for both Barrett's esophagus and esophageal adenocarcinoma. We propose that reactivation of latent developmental signaling a pathway within the esophagus is a fundamental requirement for Barrett's metaplasia. This project will expand on our previous work that identified Hedgehog (Hh) pathway activation in Barrett's esophagus and demonstrated that forced Hh expression and subsequent downstream Bone morphogenetic protein (BMP) 4 signaling induces columnar changes in esophageal epithelium. We previously identified SOX9, a transcription factor expressed in the embryonic esophagus, as a Hh-BMP4 target gene that is upregulated in Barrett's esophagus and induces expression of columnar genes. We have now identified a second Hh-BMP4 target gene and embryonic esophageal transcription factor, FOXA2, to be expressed in Barrett's esophagus but not in normal adult esophageal epithelium. Our hypothesis is that expression of these two embryonic transcription factors, activated by Hh and BMP4 signaling induced by gastroesophageal reflux disease (GERD) is required for the development of columnar metaplasia. We will attempt to further define the role of Hh and BMP4 signaling in Barrett's esophagus through three specific aims: Aim 1) To delineate how BMP4 upregulates SOX9 and FOXA2 expression in human esophageal epithelial cells; Aim 2) To determine if sequential and combinatorial stable expression of SOX9, FOXA2, and CDX2 in esophageal squamous epithelial cells results in phenotypic features of Barrett's metaplasia; and Aim 3) To determine in vivo expression levels of Hh and BMP4 pathway proteins and their downstream targets (SOX9, FOXA2) and CDX2 in biopsy samples of esophageal squamous epithelium from GERD patients with and without Barrett's esophagus. Through these studies, we expect to define the role Hh-BMP4 signaling plays in establishing columnar metaplasia and determine if there are differences in Hh-BMP4 signaling between GERD patients with and without Barrett's esophagus. These findings would contribute towards our objectives of 1) identifying specific molecular markers that can be used to predict which GERD patients would benefit from aggressive anti-reflux therapies to prevent Barrett's esophagus; 2) designing a molecularly targeted chemopreventative or therapeutic strategy for Barrett's esophagus and esophageal adenocarcinoma; and 3) validating our innovative approach of applying developmental biology to the understanding of Barrett's metaplasia.

描述（由申请人提供）：巴雷特的食管，远端食管上皮从鳞状到柱状的变化，显着增加了食管腺癌的风险，食管腺癌是该国食管癌的普遍形式。了解食管上皮柱状化生的分子机制对于设计分子靶向化学预防剂或治疗策略至关重要。我们认为，潜在发育信号的重新激活食管内的途径是巴雷特化学的基本要求。该项目将扩大我们以前的工作，该工作确定了Barrett食管中刺猬（HH）途径的激活，并证明强迫HH表达和随后的下游骨形态发生蛋白（BMP）4信号传导引起食管上皮食管的柱状变化。我们先前鉴定出在胚胎食管中表达的转录因子SOX9为HH-BMP4靶基因，该基因在Barrett的食管中上调并诱导柱状基因的表达。现在，我们已经确定了第二个HH-BMP4靶基因和胚胎食管转录因子FOXA2，将在Barrett的食管中表达，但在正常的成年成年食管上皮中不表达。我们的假设是，这两个胚胎转录因子的表达是由HH和BMP4信号激活的胃食管反流疾病（GERD）的表达，才能开发柱状化Metaplasia。我们将尝试通过三个特定目标进一步定义HH和BMP4信号传导在Barrett食管中的作用：目标1）描绘BMP4如何上调Sox9和FoxA2在人类食管上皮细胞中的表达；目标2）确定食管鳞状上皮细胞中Sox9，FoxA2和CDX2的顺序和组合稳定表达是否会导致Barrett化生的表型特征；目标3）确定HH和BMP4途径蛋白的体内表达水平及其下游靶标（SOX9，FOXA2）和CDX2在来自有或没有Barrett食管的GERD患者的食管鳞状上皮的活检样本中。通过这些研究，我们期望定义HH-BMP4信号传导在建立柱状化生中的作用，并确定患有和没有巴雷特食管的GERD患者之间HH-BMP4信号的差异。这些发现将有助于我们的目标1）确定可用于预测哪些GERD患者将受益于侵略性抗反复疗法的特定分子标记，以防止Barrett的食管； 2）设计针对巴雷特食管和食管腺癌的分子靶向化学预防或治疗策略； 3）验证我们将发育生物学应用于理解巴雷特化学的创新方法。