Ulcerative colitis-associated cancer and its prevention

溃疡性结肠炎相关癌症及其预防

基本信息

批准号：
7430444
负责人：
Guang-Yu Yang
金额：
$ 21.68万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7430444
关键词：
3-nitrotyrosine 8-hydroxy-2&apos -deoxyguanosine 8-oxo-7,8-dihydrodeoxyguanine Abbreviations Acetylcysteine Anemia Antioxidants Arachidonate 5-Lipoxygenase Arachidonic Acids Automobile Driving Biochemical Carcinoma Cell Proliferation Cell Survival Cells Chemoprevention Chemopreventive Agent Chronic Chronic Disease Colon Coxibs DNA Damage DNA Repair Enzymes DNA glycosylase Development Dextran Sulfate Dietary Iron Dinoprostone Disease Dysplasia Effectiveness Endothelial Cells Enzyme Inhibitor Drugs Enzyme Inhibitors Event Exhibits Genetic Genus Cola Goals Hemorrhage Human Inflammation Inflammatory Injury Iron Knockout Mice Leukocytes Leukotriene B4 Lipids Lipoxygenase Inhibitors Malignant Neoplasms Mediating Modeling Mucinous Mucositis Mus NADPH Oxidase Nitric Oxide Nitric Oxide Synthase Nitrogen Oxidative Stress Oxygen Pathway interactions Patients Play Post-Translational Protein Processing Predisposition Prevention Process Research Personnel Role Sampling Sodium Sodium Dextran Sulfate Supplementation Testing Tocopherols Toxic effect Ulcer Ulcerative Colitis Vitamin E Water Wild Type Mouse Yang Zileuton aminoguanidine angiogenesis base cancer risk carcinogenesis celecoxib colitis associated cancer concept cyclooxygenase 2 human NOS2A protein human NOS3 protein inhibitor/antagonist knockout gene macrophage mouse model neutrophil oxidative DNA damage programs tumor

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to provide a mechanistic basis for the prevention of Ulcerative colitis (UC)-associated carcinogenesis (UC-Ca). Our unique UC-Ca mouse model will be used to test the hypothesis that leukocyte-NADPH oxidase and endothelial nitric oxide synthase (eNOS) play central roles in UC-Ca by driving nitro-oxidative stress-caused genetic damage and angiogenesis, and by causing cell hyperproliferation via the overproduction of prostaglandin E2 (PGE2) and Leukotriene B4 (LTB4), with the following specific aims: 1. To study the role of leukocyte-generated oxidative stress and associated DNA damage in UC-Ca by using gp91phox (leukocyte NADPH oxidase) and Ogg1 (8-hydroxydeoxyguanine DNA glycosylase) deficient mice. We will test the hypothesis that gp91phox is vital for causing oxidative DNA damage and UC-Ca, and that Ogg1 protects from UC-Ca, using gene knockout mice in the UC-Ca model. 2. To test the hypothesis that eNOS plays a key role in UC-Ca by driving nitro-oxidative stress-caused DNA damage and by promoting angiogenesis, iNOS deficient mice exhibited no difference in susceptibility to UC-Ca or nitrotyrosine formation in our model, but eNOS was expressed in active inflammatory cells. The roles of eNOS or both eNOS/iNOS in UC-Ca will be studied using an eNOS (-/-)mice and the non-selective NOS inhibitor aminoguanidine. 3. To test the hypothesis that inflammation-induced LTB4 and PGE2 overproduction contributes to UCCa by studying the effect of the combination of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5- LOX) inhibitors. COX-2 inhibition exacerbates UC, possibly via the shunting of arachidonic acid substrate to the LTB4 pathway and increasing inflammatory injury. The combination of 5-LOX- and COX-2-specific inhibitors may overcome this problem in the treatment of UC patients. This concept will be tested in our UC-Ca model. 4. To determine the effectiveness of water-soluble and lipid-soluble antioxidants and their combination as a chemopreventive approach against UC-Ca in wild type and Ogg1(-/-) mice. The combination of vitamin E and N-acetylcysteine (NAC) may exert synergistic or additive effects against nitro-oxidative stress, inflammation, and UC-Ca. This concept will be investigated using our UC-Ca model as well as using Ogg1 knockout mice.

描述（由申请人提供）：该项目的长期目标是为预防溃疡性结肠炎（UC）相关癌变（UC-Ca）提供机制基础。我们独特的 UC-Ca 小鼠模型将用于检验白细胞-NADPH 氧化酶和内皮一氧化氮合酶 (eNOS) 在 UC-Ca 中发挥核心作用的假设，它们通过驱动硝基氧化应激引起的遗传损伤和血管生成，并通过引起通过前列腺素 E2 (PGE2) 和白三烯 B4 (LTB4) 的过量产生来促进细胞过度增殖，具体目标如下： 1. 使用 gp91phox（白细胞 NADPH 氧化酶）和 Ogg1（8-羟基脱氧鸟嘌呤 DNA 糖基化酶）缺陷小鼠研究白细胞产生的氧化应激和相关 DNA 损伤在 UC-Ca 中的作用。我们将使用 UC-Ca 模型中的基因敲除小鼠来检验以下假设：gp91phox 对于引起氧化性 DNA 损伤和 UC-Ca 至关重要，而 Ogg1 可以防止 UC-Ca。 2. 为了检验 eNOS 通过驱动硝基氧化应激引起的 DNA 损伤和促进血管生成在 UC-Ca 中发挥关键作用的假设，iNOS 缺陷小鼠在我们的模型中对 UC-Ca 或硝基酪氨酸形成的易感性没有表现出差异，但 eNOS 在活跃的炎症细胞中表达。将使用 eNOS (-/-) 小鼠和非选择性 NOS 抑制剂氨基胍来研究 eNOS 或 eNOS/iNOS 在 UC-Ca 中的作用。 3. 通过研究环氧合酶-2 (COX-2) 和 5-脂氧合酶 (5-LOX) 抑制剂组合的作用，检验炎症诱导的 LTB4 和 PGE2 过量产生导致 UCCa 的假设。 COX-2 抑制可能通过将花生四烯酸底物分流至 LTB4 途径并增加炎症损伤而加剧 UC。 5-LOX-和COX-2特异性抑制剂的组合可能会克服UC患者治疗中的这个问题。这个概念将在我们的 UC-Ca 模型中进行测试。 4. 确定水溶性和脂溶性抗氧化剂及其组合作为野生型和 Ogg1(-/-) 小鼠中 UC-Ca 化学预防方法的有效性。维生素 E 和 N-乙酰半胱氨酸 (NAC) 的组合可能对硝基氧化应激、炎症和 UC-Ca 发挥协同或相加作用。我们将使用我们的 UC-Ca 模型以及 Ogg1 敲除小鼠对这一概念进行研究。