In Vivo Role of Nitric Oxide in Muscosal Inflammation and Cancer

一氧化氮在粘膜炎症和癌症中的体内作用

• 批准号: 7514463
• 负责人: DAVID B SCHAUER
• 金额: $ 31.04万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7514463
• 关键词: Adoptive Transfer; Biological Assay; Biological Markers; Biological Models; C57BL/6 Mouse; Cells; Chemicals; Citrobacter rodentium; Colitis; Colon; Computer Simulation; DNA Repair; Direct Repeats; Enzymes; Epithelial Cells; Eragrostis; Event; Genes; Genetic Recombination; Helicobacter; Helicobacter hepaticus; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Large Intestine; Lesion; Malignant Neoplasms; Modeling; Mucositis; Mus; Mutagenesis; Mutant Strains Mice; Nitric Oxide; Nitrites; Oxidative Stress; Reporter; Role; Series; Somatic Mutation; Specimen; T-Lymphocyte; Transgenes; Translating; base; cancer risk; carcinogenesis; colitis associated cancer; homologous recombination; human NOS2A protein; in vivo; macrophage; man; mouse model; neutrophil; novel; prevent; programs; research study

Project 4 In order to investigate the mechanisms by which inflammation, oxidative stress, and nitric oxide in particular contribute to cancer risk, we have developed a series of mouse models of colitis and colitis-associated cancer. We will use highly susceptible compound mutant mice deficient for interleukin 10 (IL10) and recombination activating gene 2 (Rag2) on a 129/SvEv background. These 129/SvEv ILIO'^Rag"'" mice develop lesions that resemble inflammatory bowel disease (IBD) and cancer when infected with Helicobacter hepaticus or after adoptive transfer with CD4*CD45RBhigh effector T cells (Teff). We will also use IL10"'" mice on a C57BL/6 background infected with Helicobacter trogontum and wild type C57BL/6 mice infected with Citrobacter rodentium. For all three mouse models, the gpt delta reporter transgene will be used to quantify and characterize somatic mutations that arise in vivo. A novel Fluorescent Yellow Direct Repeat (FYDR) transgene will also be generated in order to quantify recombination events in vivo. We will characterize the role of inducible nitric oxide synthase (iNOS) in 129/SvEv ILIO^'Rag"'" mice infected with H. hepaticus that develops a rapid onset of colitis-associated cancer, C57BL/6 IL10"'" mice infected with H. trogontum that develops IBD, and C57BL/6 mice infected with C. rodentium that develops a self-limiting colitis. This will be accomplished by pharmacologic inhibition of NOS enzymes as well as by crossing our C57BL/6 models with iNOS"'" mice. Depletion experiments will also be carried out to ascertain the role of neutrophils and macrophages in colitis and cancer in these model systems. These experiments will provide specimens for the other Projects in this Program in order to validate computational models, characterize chemical biomarkers, and establish the role of DNA damage and repair in mutagenesis. By establishing the role of nitric oxide produced by inflammatory cells and by epithelial cells in the large intestine, we will gain a better understanding of the mechanistic basis of cancer risk in IBD, and in mucosal inflammation in general. These studies and the interactions with the other Projects in the Program should translate into newstrategies to prevent the initiation or delay the progression of inflammation-associated cancer.

项目4为了研究炎症、氧化应激、 尤其是一氧化氮会增加癌症风险，我们已经开发了一系列小鼠实验， 结肠炎和结肠炎相关癌症的模型。我们将使用高度敏感的复合突变体 白细胞介素10（IL 10）和重组激活基因2（Rag 2）缺陷的小鼠， 129/SvEv背景。这些129/SvEv IL 10 + Rag+小鼠发展出类似于 炎症性肠病（IBD）和癌症，当感染肝螺杆菌或 用CD 4 * CD 45 RB高效应T细胞（Teff）过继转移后。我们还将使用IL 10+小鼠 在感染幽门螺杆菌的C57 BL/6背景和野生型C57 BL/6小鼠上 感染了啮齿类柠檬酸杆菌对于所有三种小鼠模型， 转基因将用于定量和表征体内产生的体细胞突变。一种新型 还将产生荧光黄色直接重复（FYDR）转基因，以便定量表达。 体内重组事件。我们将描述诱导型一氧化氮合酶的作用 （iNOS）在感染H.肝细胞性肝炎， 结肠炎相关癌，感染H.发展IBD的trogontum， C57 BL/6小鼠感染C.会发展成自限性结肠炎这将是 通过药理学抑制NOS酶以及通过交叉我们的C57 BL/6 用iNOS小鼠模型。还将进行贫化实验，以确定 嗜中性粒细胞和巨噬细胞在这些模型系统中的结肠炎和癌症中的作用。这些实验 将为本计划中的其他项目提供样本，以验证计算 模型，表征化学生物标志物，并建立DNA损伤和修复在 诱变通过确定炎症细胞产生的一氧化氮的作用， 在大肠上皮细胞，我们将获得更好的了解机制， IBD和一般粘膜炎症的癌症风险基础。这些研究和 与计划中其他项目的互动应转化为新的战略， 预防炎症相关癌症的发生或延迟炎症相关癌症的进展。