Ulcerative colitis-associated cancer and its prevention

溃疡性结肠炎相关癌症及其预防

• 批准号: 7256524
• 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
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256524
• 关键词: 3-nitrotyrosine; 8-hydroxy-2' -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

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与溃疡性结肠炎（UC）相关的致癌作用（UC-CA）提供机械基础。我们独特的UC-CA小鼠模型将用于检验以下假设：白细胞 - 纳德氧化酶和内皮氧化物氧化物合酶（ENOS）通过驱动氮氧化应激造成的遗传损伤和血管生成，并通过使细胞过度生产（Prostag2）（Prostag2）（Prostagllandin e2）（Prostaglandin e2）（Prostaglandin e2（Prostaglandin e2）通过驱动氮氧化遗传损伤和血管生成，从而在UC-CA中起着重要作用。 （LTB4），具有以下特定目的： 1。通过使用GP91Phox（白细胞NADPH氧化酶）和OGG1（8-羟基氧基鸟嘌呤DNA DNA DNA糖基化酶），研究白细胞生成的氧化应激和相关DNA损伤的作用。我们将检验以下假设：GP91Phox对于引起氧化DNA损伤和UC-CA至关重要，并且使用UC-CA模型中的基因基因敲除小鼠，OGG1可以保护UC-CA。 2。通过驱动硝基氧化应激引起的DNA损伤并促进血管生成，eNOS在UC-CA中起关键作用的假设，INOS缺乏小鼠在我们模型中对UC-CA或硝基酪氨酸形成的易感性没有差异，但是在我们的模型中，ENOS在活跃的炎症细胞中表现出来。将使用eNOS（ - / - ）小鼠和非选择性的NOS抑制剂氨基瓜氨酸来研究eNOS或ENOS/INOS在UC-CA中的作用。 3。为了测试炎症诱导的LTB4和PGE2过量产生的假设，通过研究环氧合酶-2（COX-2）和5-脂氧合酶（5-洛克斯）抑制剂的效果来促进UCCA。 COX-2抑制作用加剧了UC，可能是通过将花生四烯酸底物分解为LTB4途径并增加炎症性损伤。 5-lox-和COX-2特异性抑制剂的组合可能会在UC患者治疗中克服这一问题。该概念将在我们的UC-CA模型中进行测试。 4。确定水溶性和脂溶性抗氧化剂的有效性，以及它们作为对野生型和OGG1（ - / - ）小鼠的UC-CA的化学预防方法的组合。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发挥协同或加性作用。该概念将使用我们的UC-CA模型以及使用OGG1敲除小鼠进行研究。