The Role of Selenium in Intestinal Inflammation and Cancer

描述(申请人提供)：胃肠道(GI)慢性炎症与结肠癌发病率增加有关。已知，炎症反应中产生的活性氧和氮物种有助于诱变。硒依赖的谷胱甘肽过氧化物酶(GPX)是参与还原过氧化氢的酶之一。GPX是保护生物膜中多不饱和脂类的基本酶。除了在GPX活性中的重要作用外，硒还可能具有单独的抗氧化和抗癌特性，并可能通过影响p38MAPK和核因子-βB而发挥抗炎作用。许多研究表明，补硒具有癌症化学预防作用；然而，硒抑制肿瘤发生的机制尚不清楚。低硒水平也与人类恰加斯病的消化形式有关，这表明硒在胃肠道炎症中发挥了作用。这个探索性/发展性研究项目的目标是使用非侵入性磁共振成像(MRI)方法，结合微型PET和生物检测来评估补硒在小鼠炎症和癌症模型中的作用。将使用两种类型的鼠标模型。第一个是克氏锥虫感染恰加斯病的小鼠模型。我们对这些小鼠进行了广泛的心脏成像研究，这些小鼠除了出现巨结肠和巨噬细胞外，还出现了心脏肥大。这种疾病包括胃肠道的炎症，而不是肿瘤的发展。第二种类型的小鼠模型是胃肠道癌。APC杂合子和Muc2/p21双突变小鼠是研究胃肠道肿瘤的良好模型。该项目将实现两个具体目标。目的1评价硒在克氏毛滴虫感染小鼠胃肠道炎症中的作用。目的2评价硒在小鼠肠癌模型肿瘤发生中的作用。在这个项目中获得的方法学发展和结果将用于指导未来旨在评估治疗剂和抗氧化剂在其他炎症性疾病和胃肠道癌症中的作用的研究。钥匙

DESCRIPTION (provided by applicant): Chronic inflammation of the gastrointestinal (GI) tract is associated with increased incidence of colon cancer. Reactive oxygen and nitrogen species, generated in response to inflammation, are known to contribute to mutagenesis. Selenium-dependent glutathione peroxidase (GPx) is one of the enzymes involved in reducing hydrogen peroxide. GPx is a fundamental enzyme for protection of polyunsaturated lipids in biological membranes. In addition to its essential role in GPx activity, selenium may have separate anti-oxidant and anti-cancer properties and may act as an anti-inflammatory agent through effects on p38 MAPK and NF-?B. A number of studies have demonstrated cancer chemopreventive effects of selenium supplementation; however, the mechanisms by which selenium suppresses tumorigenesis are still unknown. Low selenium levels are also associated with the digestive form of Chagas' disease in humans suggesting a role for selenium in inflammation of the GI tract. The goals of this exploratory/developmental research project are to use noninvasive magnetic resonance imaging (MRI) methods in combination with micro-PET and biological assays to evaluate the role of selenium supplementation in mouse models of inflammation and cancer. Two types of mouse models will be used. The first is the Trypanosoma cruzi infected mouse model of Chagas' disease. We have performed extensive cardiac imaging studies on these mice which develop cardiomegaly in addition to megacolon and megaesophagus. This disease involves inflammation of the GI tract without the development of tumors. The second type of mouse model is GI tract cancer. The Apc heterozygote and Muc2/p21 double mutation mice are excellent models available for the study of tumors in the GI tract. Two specific aims will be addressed in this project. Aim 1 will evaluate the role of selenium in GI Tract inflammation in mice infected with T. cruzi. Aim 2 will evaluate the role of selenium in development of tumors in mouse models of intestinal cancer. The methodology developments and results acquired in this project will be used to guide future studies aimed at evaluating the role of therapeutic agents and anti-oxidants in other inflammatory diseases and cancer of the GI tract. KEY