The Role of Selenium in Intestinal Inflammation and Cancer

描述（由申请人提供）：胃肠道慢性炎症与结肠癌发病率增加有关。在炎症反应中产生的活性氧和活性氮被认为有助于诱变。硒依赖性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质的基本酶。除了在GPx活性中发挥重要作用外，硒还可能具有抗氧化和抗癌特性，并可能通过影响p38 MAPK和NF- B而发挥抗炎作用。许多研究已经证明了补充硒的癌症化学预防作用；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起作用。本探索性/发展性研究项目的目标是利用无创磁共振成像（MRI）方法结合微pet和生物检测来评估硒补充剂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。首先是克氏锥虫感染的恰加斯病小鼠模型。我们对这些小鼠进行了广泛的心脏成像研究，这些小鼠除了巨结肠和巨食管外，还出现了心脏肥大。这种疾病涉及胃肠道炎症，但没有肿瘤的发展。第二种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。本项目将解决两个具体目标。目的1将评价硒在克氏锥虫感染小鼠胃肠道炎症中的作用。目的2将在小鼠肠癌模型中评估硒在肿瘤发展中的作用。本项目取得的方法学进展和结果将用于指导未来的研究，旨在评估治疗药物和抗氧化剂在其他炎症性疾病和胃肠道癌症中的作用。关键

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