Insulin/IGF-1 Pathway in Barrett's Esophagus

Barrett 食管中的胰岛素/IGF-1 通路

基本信息

批准号：
7661604
负责人：
AMITABH CHAK
金额：
$ 22.48万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-21 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7661604
关键词：
Aberrant DNA Methylation Address Adenocarcinoma Advisory Committees Affect Animals Antibodies Apoptosis Barrett Epithelium Barrett Esophagus Binding Binding Proteins Biological Assay Biological Markers Biopsy Candidate Disease Gene Carbohydrates Case-Control Studies Cell Proliferation Cell Survival Complex Country Coupled Development Diet Dietary Factors Disease Endocrine Epigenetic Process Epithelial Epithelial Cells Epithelium Esophageal Esophageal Adenocarcinoma Fatty acid glycerol esters Frequencies Future Gastroesophageal reflux disease Gene Silencing Genes Genetic Goals Growth Growth Factor Homeostasis Hormones Hyperinsulinism IGFBP3 gene Immunochemistry Incidence Individual Inflammation Mediators Insulin Insulin Receptor Insulin Resistance Insulin-Like Growth Factor I Insulin-Like Growth-Factor-Binding Proteins Insulin-Like-Growth Factor I Receptor Intestinal Mucosa Intestines Lead Link Malignant Neoplasms Malignant neoplasm of esophagus Measures Mediator of activation protein Metaplastic Methods Methylation Modeling Molecular Mucous Membrane Mutation Neoplasms Neoplastic Cell Transformation Obesity Obesity associated cancer Odds Ratio Pathway interactions Patients Pilot Projects Process Proto-Oncogene Proteins c-akt Public Health Reflux Regulation Research Risk Risk Factors Role Signal Pathway Signal Transduction Somatomedins Squamous Epithelium Stratification Surrogate Markers Therapeutic Agents Tissue Inhibitor of Metalloproteinase-3 Translational Research Tumor Tissue Tyrosine Tyrosine Phosphorylation United States United States National Institutes of Health Upper arm Visceral base carcinogenesis case control fasting glucose human FRAP1 protein indexing insulin receptor substrate 1 protein neoplastic outcome forecast pandemic disease paracrine pressure tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The alarming rise in esophageal adenocarcinoma incidence over the past 3 decades coupled with a poor prognosis make this cancer an important national public health issue. Adenocarcinoma of the esophagus arises in Barrett's esophagus, a pre- neoplastic metaplastic transformation of the squamous epithelium that is closely associated with gastroesophageal reflux. We, and others, have found that Barrett's esophagus and esophageal adenocarcinoma are independently linked to obesity. The increased incidence of these diseases is partially attributable to a pandemic of obesity in this country. Increased levels of insulin and the Type 1 insulin growth factor are postulated to be a key mechanistic link between obesity, the Western diet, and carcinogenesis in other cancers. Our central hypothesis is that "hyperinsulinemia and high levels of Type 1 insulin growth factor (IGF-1) possibly related to the Western diet in susceptible individuals contribute to genetic and epigenetic changes in the esophageal epithelium that are key to the development of Barrett's esophagus and its subsequent progression to esophageal adenocarcinoma". Components of this complex hypothesis will be explored in this case control study whose aims are -- to 1. Calculate insulin resistance and measure free IGF-1; 2. Assay phosphorylated insulin receptor substrate- 1 (phos-IRS-1) immunostaining; and 3. Assess for aberrant methylation of selected candidate genes in Barrett's esophagus patients and control subjects. Successful conduct of this pilot study will enable future studies which are: a) examining the interaction of the insulin/IGF proliferative pathway with gastreoesophageal reflux in esophageal carcinogenesis; b) studies to identify important dietary factors in the development of Barrett's esophagus; c) risk stratification of Barrett's esophagus based on biomarkers; and d) trials of potential therapeutic agents based on the insulin/IGF pathway. The research proposed in this application will determine whether increased level of the hormones, insulin and insulin growth factor-1, explain the link between obesity and adenocarcinoma of the esophagus. It will also enable studies to identify factors in the Western diet that might predispose to the development of Barrett's esophagus and cancer. Furthermore, this research will identify biomarkers that may lead to methods for identifying people with Barrett's esophagus who are at risk for developing cancer and lead to treatments aimed at halting or reversing this process.

描述（由申请人提供）：在过去30年中，食管腺癌发病率的令人震惊的增长加上预后不良，使该癌症成为重要的国家公共卫生问题。食管的腺癌发生在Barrett的食道，这是鳞状上皮的一种肿瘤前化生型转化，与胃食管反流密切相关。我们和其他人发现，巴雷特的食管和食管腺癌与肥胖独立联系。这些疾病的发病率增加部分归因于这个国家的肥胖症大流行。胰岛素水平的增加和1型胰岛素生长因子被认为是其他癌症中肥胖，西方饮食和癌变之间的关键机械联系。我们的核心假设是“易感个体中的高胰岛素血症和高水平的1型胰岛素生长因子（IGF-1）可能与西方饮食有关，这有助于食管上皮的遗传和表观遗传学变化，这是Barrett食管和食管食管的至关重要的。随后发展为食管腺癌的进展”。在此案例控制研究中将探讨该复杂假设的组成部分，其目的是 - 至1。计算胰岛素抵抗并测量游离IGF-1； 2。测定磷酸化的胰岛素受体底物-1（Phos-IRS-1）免疫染色；和3。评估Barrett食管患者和对照组中所选候选基因的异常甲基化。这项试验研究的成功进行将实现未来的研究：a）研究胰岛素/IGF增殖途径与食管癌发生中胃食管反流的相互作用； b）研究在巴雷特食管发展中确定重要的饮食因素； c）基于生物标志物的巴雷特食管的风险分层； d）基于胰岛素/IGF途径的潜在治疗剂的试验。本应用中提出的研究将确定激素，胰岛素和胰岛素生长因子1的水平是否增加了，解释了食管的肥胖与腺癌之间的联系。它还将使研究能够确定西方饮食中的因素，这些因素可能会易受巴雷特食管和癌症的发展。此外，这项研究将确定可能导致识别巴雷特食管患者患癌症风险并导致旨在停止或逆转这一过程的治疗方法的生物标志物。