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：参见说明。说明申请的广泛、长期目标和具体目标，并提及 该项目（即，与原子能机构的使命相关）。简要描述研究设计和实现这些目标的方法。描述 你将用来追求这些目标的基本原理和技术。 此外，用两三句话，用通俗的语言描述这项研究与公共卫生的相关性。如果申请得到资助， 这样的描述将成为公开信息。因此，不包括专有/机密信息。不要超过空间 提供了 胃食管反流病（GERD）影响超过十分之一的40岁以上的成年人， 每四个60岁以上的成年人中就有一个大约10%的GERD患者发展为巴雷特食管（BE）， 与食管腺癌发生风险增加近30-125倍相关 （EA）。从BE进展到发育不良和EA的机制尚不清楚。因此，我们将研究 一些可能参与这一进程的途径。 活性氧（ROS）在BE和EA中升高，并且可能在BE和EA的进展中起关键作用。 从BE到EA。我们发现一种新的NADPH氧化酶NOX 5-S亚型在EA细胞系中过表达， EA组织和BE粘膜高度异型增生。NOX 5-S首次在人胎肾中发现 并且在其它组织中没有描述。在SEG 1 EA细胞中，脉冲酸暴露导致 NOX 5-S，增加H2 O2的产生。N 0X 5-S衍生的ROS有助于增加细胞增殖， 减少SEG 1细胞的凋亡。然而，酸诱导的NOX 5-S上调和 NOX 5-S依赖的细胞增殖增加和细胞凋亡减少尚未完全了解。 因此，我们将检验酸暴露通过激活NADPH氧化酶来上调NADPH氧化酶的假设。 Barrett化生细胞中的Rho激酶和MAP激酶，导致自由基的过度产生， 反过来可能通过激活核因子κ B进一步增强NADPH氧化酶的表达 （NF-kB）。此外，ROS可能上调细胞周期蛋白D1和死亡结构域沉默物（SODD）。 细胞周期蛋白D1和SODD的上调将增加这些细胞中的细胞增殖并减少细胞凋亡。 因此，BE患者中存在的持续性酸反流可能导致高水平的ROS，细胞增殖， 增殖和凋亡减少，这可能导致DNA损伤和突变增加， 有助于从BE发展到发育不良和EA。 为了验证这一假设，我们将：1）检查酸诱导表达的信号转导途径 在BE细胞系、Barrett粘膜活组织检查和EA细胞（SEG 1、FLO和OE 33）中的NADPH氧化酶。 我们将重点讨论Rho激酶、MAP激酶和NF-kB的作用。2)研究NADPH的作用机制 氧化酶依赖性的细胞增殖增加和细胞凋亡减少，集中在作用 细胞周期蛋白D1和SODD，并检查NADPH氧化酶衍生的ROS是否引起DNA损伤。3)审查 NOX 5-S发挥功能所需的调节蛋白，重点是Rac 1和p22 phox。 对酸诱导NADPH上调的信号转导途径的进一步理解 氧化酶，导致细胞增殖增加和凋亡减少，可能提供了一种合理的方法， 预防EA的发展。此外，NOX 5-S可能是早期检测的潜在生物标志物。 食管发育不良我们的模型也可能适用于其他炎症相关的癌症。