Ulcerative colitis-associated cancer and its prevention

描述（由申请人提供）：本项目的长期目标是为预防溃疡性结肠炎（UC）相关致癌作用（UC-Ca）提供机制基础。我们独特的UC-Ca小鼠模型将用于测试白细胞-NADPH氧化酶和内皮型一氧化氮合酶（eNOS）通过驱动硝基氧化应激引起的遗传损伤和血管生成，以及通过过度生产前列腺素E2（PGE 2）和白三烯B4（LTB 4）引起细胞过度增殖，在UC-Ca中发挥核心作用的假设，具体目标如下： 1.目的：利用gp 91 phox（白细胞NADPH氧化酶）和Ogg 1（8-羟基脱氧鸟嘌呤DNA糖基化酶）缺陷小鼠，研究白细胞氧化应激及相关DNA损伤在UC Ca发病中的作用。我们将使用基因敲除小鼠在UC-Ca模型中测试gp 91 phox对引起氧化性DNA损伤和UC-Ca至关重要以及Ogg 1保护免受UC-Ca的假设。 2.为了验证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中起关键作用的假设，在我们的模型中，iNOS缺陷小鼠对UC-Ca或硝基酪氨酸形成的易感性没有差异，但eNOS在活性炎症细胞中表达。将使用eNOS（-/-）小鼠和非选择性NOS抑制剂氨基胍研究eNOS或eNOS/iNOS两者在UC-Ca中的作用。 3.通过研究环氧合酶-2（考克斯-2）和5-脂氧合酶（5- LOX）抑制剂的联合作用，验证炎症诱导的LTB 4和PGE 2过度产生导致UCCa的假设。考克斯-2抑制可能通过花生四烯酸底物分流至LTB 4通路并增加炎性损伤而加重UC。5-LOX-和考克斯-2-特异性抑制剂的组合可以克服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Ogg 1（-/-）小鼠中UC-Ca的化学预防方法的有效性。维生素E和N-乙酰半胱氨酸（NAC）的组合可以对硝基氧化应激，炎症和UC-Ca发挥协同或相加作用。这一概念将使用我们的UC-Ca模型以及使用Ogg 1敲除小鼠进行研究。

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.