Mechanisms of Tumorigenic Transformation of Barretts Esophagus

Barretts食管致瘤转化机制

基本信息

批准号：
9326930
负责人：
ALEXANDER I. ZAIKA
金额：
$ 8.81万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9326930
关键词：
Accounting Acids Affect Anchorage-Independent Growth Animal Model Apoptosis Apoptotic Barrett Esophagus Bile fluid Biological Process Cancerous Cell Aging Cell Cycle Cell physiology Cells Cellular Stress Characteristics Chronic Clinical Complement Complex DNA Damage DNA Repair Data Development Disease Disease susceptibility Drug usage Duodenum Esophageal Esophageal Adenocarcinoma Esophageal Neoplasms Esophageal mucous membrane Esophagus Etiology Event Gastric Juice Gastroesophageal reflux disease Genetic Transcription Health Histologic Human In Vitro Incidence Inflammation Inflammatory Response Injury Knockout Mice Lead Lesion MAPK14 gene Malignant - descriptor Malignant Neoplasms Medical Metaplasia Molecular Mutate Mutation NF-kappa B Normal Cell Oncoproteins Oxidative Regulation Pathologic Pathology Pathway interactions Patient risk Patients Pharmaceutical Preparations Play Population Premalignant Preventive therapy Production Protein Family Protein Isoforms Protein p53 Proteins Proto-Oncogenes Proton Pump Inhibitors Reflux Regulation Research Risk Factors Role TP53 gene Testing Tissues Treatment Efficacy Tumor Suppressor Proteins Tumorigenicity United States Up-Regulation Western World base bile salts cell immortalization cost effective curative treatments cytokine human data human tissue immortalized cell improved in vivo inhibitor/antagonist innovation insight member metaplastic cell transformation mouse model novel novel diagnostics novel therapeutic intervention novel therapeutics overexpression oxidative DNA damage protein p73 screening standard of care tumor tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY/ABSTRACT Esophageal adenocarcinoma (EAC) is a serious clinical problem due to its rapidly increasing incidence rate, and the limited treatment options currently available. This disease has now overtaken other histological types of esophageal tumors in the US. The major risk factor for EAC is gastroesophageal reflux disease (GERD), which affects 10 to 20% of the US population. Under conditions of GERD, esophageal cells are ex- posed to acidic gastric juice mixed with duodenal bile salts. The reflux exposure causes chronic inflammation, and excessive oxidative DNA damage, resulting in the accumulation of tumorigenic alterations and progression to EAC through Barrett's metaplasia (BE). However, the precise molecular events underlying the malignant transformation of esophageal cells remain poorly understood, thereby limiting the identification of targets for screening at risk patients and the development of new therapies for esophageal tumors. We have developed an innovative hypothesis to investigate tumorigenic transformation of esophageal cells in conditions of esophageal reflux injury. This hypothesis is supported by strong preliminary data from human tissues, animal models, and extensive in vitro studies. We have demonstrated that the 6Np73 protein plays a critical role in esophageal tumorigenesis by inhibiting key tumor suppressor proteins in Barrett's esophageal cells exposed to chronic gastroesophageal reflux. We have also identified pathological factors that lead to 6Np73 activation. We will build on these findings to further investigate the role played by 6Np73 and other members of the p53 protein family in the progression to esophageal adenocarcinoma. In aim 1, we will dissect the mechanisms of 6Np73 upregulation during progression to EAC. In aim 2, we will investigate esophageal tumorigenesis in vivo. We will employ novel mouse model of gastroesophageal reflux injury and esophageal organotypic cul- tures to recapitulate human GERD-associated pathology and dissect the function of 6Np73. These studies will be complemented with analyses of human esophageal precancerous and cancerous lesions. In aim 3, we will explore the biological functions in the regulation of oxidative DNA damage induced by gastroesophageal reflux. Our findings will have a strong impact on the understanding of multistep tumorigenesis associated with GERD and BE. Importantly, our results could help to reveal potential risk factors for esophageal tumor devel- opment and lay the groundwork for development of novel chemotherapeutic approaches in at risk patients with GERDand BE.

项目概要/摘要食管腺癌（EAC）因其发病率迅速增加而成为一个严重的临床问题率以及目前可用的治疗选择有限。这种疾病现已超过其他组织学疾病美国食管肿瘤的类型。 EAC的主要危险因素是胃食管反流病 (GERD)，影响 10% 至 20% 的美国人口。在 GERD 的条件下，食管细胞酸性胃液与十二指肠胆汁盐混合。反流暴露会导致慢性炎症，和过度的氧化DNA损伤，导致致瘤改变和进展的积累通过 Barrett 化生 (BE) 到达 EAC。然而，恶性疾病背后的精确分子事件食管细胞的转化仍然知之甚少，从而限制了目标的识别筛查高危患者并开发食管肿瘤新疗法。我们提出了一个创新的假设来研究食管细胞的致瘤转化在食管反流损伤的情况下。这一假设得到了人类强有力的初步数据的支持组织、动物模型和广泛的体外研究。我们已经证明 6Np73 蛋白起着通过抑制巴雷特食管中的关键肿瘤抑制蛋白在食管肿瘤发生中发挥关键作用细胞暴露于慢性胃食管反流。我们还确定了导致 6Np73激活。我们将在这些发现的基础上进一步调查 6Np73 和其他成员所发挥的作用 p53 蛋白家族在食管腺癌进展中的作用。在目标 1 中，我们将剖析其机制进展为 EAC 期间 6Np73 上调。在目标 2 中，我们将研究食管肿瘤的发生体内。我们将采用新型小鼠胃食管反流损伤模型和食管器官型培养物重现人类 GERD 相关病理学并剖析 6Np73 的功能。这些研究将补充人类食管癌前病变和癌病变的分析。在目标 3 中，我们将探讨胃食管反流引起的氧化DNA损伤的调节生物学功能。我们的研究结果将对与相关的多步骤肿瘤发生的理解产生重大影响 GERD 和 BE。重要的是，我们的结果可能有助于揭示食管肿瘤发展的潜在危险因素。为高危患者开发新的化疗方法奠定基础 GERD 和 BE。