Ulcerative colitis-associated cancer and its prevention

描述(申请人提供)：该项目的长期目标是为预防溃疡性结肠炎(UC)相关性癌变(UC-Ca)提供机制基础。我们独特的UC-Ca小鼠模型将被用来检验这一假设，即白细胞-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导致的遗传损伤和血管生成，以及通过过度产生前列腺素E2(PGE2)和白三烯B4(LTB4)而导致细胞过度增殖，在UC-Ca中发挥核心作用，具体目的如下： 1.利用gp91Phox(白细胞NADPH氧化酶)和Ogg1(8-羟基脱氧鸟嘌呤DNA糖基酶)缺陷小鼠，研究白细胞产生的氧化应激及相关DNA损伤在UC-Ca发病中的作用。我们将使用UC-Ca模型中的基因敲除小鼠来验证这一假设，即gp91Phox对于导致DNA氧化损伤和UC-Ca至关重要，并且Ogg1保护UC-Ca免受UC-Ca的影响。 2.为了验证eNOS通过促进硝基氧化应激引起的DNA损伤和促进血管生成而在UC-Ca中起关键作用的假说，在我们的模型中，iNOS缺陷小鼠对UC-Ca和硝基酪氨酸形成的易感性没有差异，但eNOS在活跃的炎症细胞中表达。ENOS或eNOS/iNOS在UC-Ca中的作用将通过eNOS(-/-)小鼠和非选择性一氧化氮合酶抑制剂氨基胍来研究。 3.通过研究环氧合酶-2(COX-2)和5-脂氧合酶(5-LOX)抑制剂的联合作用，验证炎症诱导的LTB4和PGE2过度产生参与UCCA的假说。COX-2抑制可能通过将花生四烯酸底物分流到LTB4途径和增加炎症损伤来加重UC。联合应用5-LOX和COX-2特异性抑制剂可在UC患者的治疗中克服这一问题。这一概念将在我们的UC-Ca模型中进行测试。 4.探讨水溶性抗氧化剂和脂溶性抗氧化剂及其组合对野生型和Ogg1(-/-)小鼠UC-Ca的化学预防作用。维生素E和N-乙酰半胱氨酸(NAC)的联合使用可能对硝基氧化应激、炎症和UC-Ca起到协同或相加的作用。这一概念将使用我们的UC-Ca模型以及Ogg1基因敲除小鼠进行研究。

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.