NADPH oxidase-associated transition from Barrett's esophagus to adenocarcinoma

NADPH 氧化酶相关的巴雷特食管向腺癌的转变

• 批准号: 8278044
• 负责人: WEIBIAO CAO
• 金额: $ 26.5万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278044
• 关键词: Acids; Adenocarcinoma; Adenocarcinoma Cell; Adult; Affect; Age-Years; American; Apoptosis; Barrett Esophagus; Biochemistry; Biological Markers; Biopsy; Cell Cycle; Cell Line; Cell Proliferation; Cells; Cessation of life; Confidential Information; Cyclic AMP-Responsive DNA-Binding Protein; Cyclin D1; DNA; DNA Damage; Data; Death Domain; Development; Dysplasia; Early Diagnosis; Enzymes; Esophageal; Esophageal Adenocarcinoma; Esophageal Intraepithelial Neoplasia; Esophageal mucous membrane; Esophagus; Fetal Kidney; Figs - dietary; Free Radicals; Funding; G1 Phase; Gastroesophageal reflux disease; Goals; Grant; Health; Human; Hydrogen Peroxide; Inferior esophageal sphincter structure; Inflammation; Inflammation Mediators; Inflammatory; Instruction; Intestinal Metaplasia; Investigation; Journals; Language; Lead; Lipids; Malignant Neoplasms; Malignant neoplasm of esophagus; Manuscripts; Mediating; Metaplasia; Metaplastic Cell; Mission; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Mitogens; Modeling; Mucous Membrane; Mutation; NADP; NADPH Oxidase; NF-kappa B; Nuclear; Oxidases; Pathway interactions; Patients; Phosphorylation; Physiologic pulse; Physiology; Platelet Activating Factor; Play; Prevention approach; Principal Investigator; Production; Protein Isoforms; Proteins; Public Health; Publishing; RNA; Reactive Oxygen Species; Reflux; Regulation; Research; Research Design; Research Methodology; Retinoblastoma Protein; Rho-associated kinase; Risk; Risk Factors; Role; STAT protein; Signal Pathway; Signal Transduction Pathway; Small Interfering RNA; Smooth Muscle; Source; Structure; Techniques; Testing; Thymidine; Tissues; Up-Regulation; cyclooxygenase 2; design; genetic regulatory protein; human CYBA protein; novel; overexpression; prevent; therapeutic target; transcription factor; tumorigenesis

DESCRIPTION: See instructions. State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. Gastroesophageal reflux disease (GERD) affects more than one in ten adults over 40 years of age and one in four adults over 60. Approximately 10% of GERD patients develop Barrett's esophagus (BE), which is associated with nearly a 30-125-fold increased risk for the development of esophageal adenocarcinoma (EA). The mechanism of progression from BE to dysplasia and to EA is unknown. We will therefore examine some of the pathways that may be involved in this progression. Reactive oxygen species (ROS) are elevated in BE and EA, and may play a key role in the progression from BE to EA. We found that a novel isoform of NADPH oxidase NOX5-S is overexpressed in EA cell lines, EA tissues, and BE mucosa with high grade dysplasia. NOX5-S was first identified in human fetal kidney and has not been described in other tissues. In SEG1 EA cells pulsed acid exposure causes upregulation of NOX5-S and increases H2O2 production. NOX5-S-derived ROS contribute to increased cell proliferation and decreased apoptosis in SEG1 cells. However, the mechanisms of acid-induced NOX5-S upregulation and NOX5-S-dependent increase in cell proliferation and decrease in apoptosis are not fully understood. We will therefore test the hypothesis that acid exposure upregulates NADPH oxidases via activation of Rho kinases and MAP kinases in Barrett's metaplastic cells, causing overproduction of free radicals, which in turn may further enhance the expression of NADPH oxidases through activation of the nuclear factor kappaB (NF-kB). In addition, ROS may upregulate cyclin D1 and the silencer of the death domain (SODD). Upregulation of cyclin D1 and SODD will increase cell proliferation and decrease apoptosis in these cells. Thus the persistent acid reflux present in BE patients may cause high levels of ROS, increased cell proliferation and decreased apoptosis, which may lead to DNA damage and increased mutations, contributing to the progression from BE to dysplasia and to EA. To test this hypothesis we will: 1) Examine the signal transduction pathway of acid-induced expression of NADPH oxidases in a BE cell line, in Barrett's mucosal biopsies, and in EA cells (SEG1, FLO, and OE33). We will focus on the role of Rho kinase, MAP kinases and NF-kB. 2) Examine the mechanisms of NADPH oxidase-dependent increase in cell proliferation and decrease in apoptosis, concentrating on the role of cyclin D1 and SODD, and examine whether NADPH oxidase-derived ROS cause DNA damage. 3) Examine the regulatory proteins required for NOX5-S to function, focusing on Rac1 and p22phox. A better understanding of the signal transduction pathway of acid induced upregulation of NADPH oxidases, leading to increased cell proliferation and decreased apoptosis, may provide a rational approach to the prevention of development of EA. In addition, NOX5-S may be a potential biomarker for early detection of esophageal dysplasia. Our model may also be applicable to other inflammation-associated cancers.

描述：请参阅说明。陈述该应用程序的广泛，长期目标和具体目标，提及 该项目（即与代理机构的任务相关）。简单地描述实现这些目标的研究设计和方法。描述 您将用来追求这些目标的基本原理和技术。 此外，用两个或三个句子描述，以简单的语言描述这项研究与公共卫生的相关性。如果申请是资助的，则 描述将成为公共信息。因此，请勿包含专有/机密信息。不要超过空间 假如。 胃食管反流疾病（GERD）影响了40岁以上的十分之一的成年人，并且 四分之一的成年人超过60岁。大约10％的GERD患者发展了Barrett的食管（BE）， 与近30-125倍增加了食管腺癌发展的风险 （ea）。从BE到发育异常到EA的进展机制尚不清楚。因此，我们将检查 该进展可能涉及的一些途径。 活性氧（ROS）在BE和EA中升高，并且可能在进展中起关键作用 从Be到Ea。我们发现，NADPH氧化酶NOX5-S的新型同工型在EA细胞系中过表达， EA组织，是具有高级发育不良的粘膜。 NOX5-S首先在人类胎儿肾脏中鉴定 并且尚未在其他组织中描述。在Seg1 EA细胞中，脉冲酸暴露会导致上调 NOX5-S并增加了H2O2的产生。 NOX5衍生的ROS有助于细胞增殖的增加和 SEG1细胞中凋亡减少。但是，酸诱导的NOX5-S上调的机制和 NOX5-S依赖性细胞增殖和凋亡减少尚未完全了解。 因此，我们将检验以下假设：酸暴露通过激活上调NADPH氧化酶 Rho激酶和Barrett化生细胞中的激酶，导致自由基的生产过多，这在 转弯可能会通过激活核因子Kappab进一步增强NADPH氧化酶的表达 （NF-KB）。此外，ROS可能会上调细胞周期蛋白D1和死亡结构域（SODD）的消音器。 细胞周期蛋白D1和SODD的上调将增加细胞增殖并减少这些细胞的凋亡。 因此，患者中存在的持续胃酸反流可能会引起高水平的ROS，细胞增加 增殖和凋亡减少，可能导致DNA损伤并增加突变， 从BE到发育不良和EA的发展促进。 为了检验该假设，我们将：1）检查酸诱导的表达的信号转导途径 BE细胞系中的NADPH氧化酶，Barrett的粘膜活检和EA细胞中（SEG1，FLO和OE33）。 我们将重点关注Rho激酶，MAP激酶和NF-KB的作用。 2）检查NADPH的机制 氧化酶依赖性增加细胞增殖和细胞凋亡的降低，集中于 Cyclin D1和SODD，检查NADPH氧化酶衍生的ROS是否引起DNA损伤。 3）检查 NOX5-S功能所需的调节蛋白，重点是Rac1和P22Phox。 更好地理解酸诱导的NADPH上调的信号转导途径 氧化酶，导致细胞增殖增加和凋亡减少，可能提供一种合理的方法 预防EA的发展。此外，NOX5-S可能是早期检测的潜在生物标志物 食管发育不全。我们的模型也可能适用于其他与炎症相关的癌症。