Selenium in gastrointestinal inflammatory diseases

硒在胃肠道炎症疾病中的作用

• 批准号: 9452052
• 负责人: Christopher S. Williams
• 金额: $ 34.37万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9452052
• 关键词: Affect; Allografting; American; Antioxidants; Apoptosis; Automobile Driving; Azoxymethane; Biology; Buffers; Colitis; Colon Carcinoma; Colonoscopy; Colorectal Cancer; DNA Damage; Data; Disease; Disease Progression; Dysplasia; Epithelial; Epithelium; F2-Isoprostanes; Functional disorder; Genetically Engineered Mouse; Growth; Homeostasis; Hyperplasia; Image; Implant; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Interleukin-10; Intestinal Mucosa; Intestines; Kinetics; Knowledge; Liver; MC38; Malignant Neoplasms; Mass Fragmentography; Mediator of activation protein; Metabolism; Modeling; Molecular; Molecular Analysis; Mucous Membrane; Mus; Mutant Strains Mice; Mutation; Neoplasms; Nutritional; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Phenotype; Plasma; Play; Production; Proteins; Protocols documentation; Publishing; Reactive Oxygen Species; Recovery; Research; Risk; Role; Selenium; Selenocysteine; Severity of illness; Sodium Dextran Sulfate; Source; Stem cells; System; Testing; Tissues; Trace Elements; Tumor Burden; Tumor Suppressor Proteins; adenoma; carcinogenesis; cell behavior; epidemiology study; experimental study; gastrointestinal; inducible gene expression; injury and repair; intestinal epithelium; macrophage; polyposis; programs; public health relevance; repaired; response; response to injury; selenium deficiency; selenoprotein; stem cell differentiation; stemness; therapeutic target; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): The contributions of Selenoprotein P (Sepp1), a major selenoprotein, to intestinal epithelial homeostasis are unknown. Selenium (Se) is an essential trace element that is incorporated into proteins as selenocysteine. Even under conditions of severe selenium deficiency, the majority of available selenium is used to synthesize Sepp1, highlighting the importance of this protein. Sepp1 has two domains: an amino redox and carboxy Se- rich domain. Sepp1 is expressed in a number of tissues including the intestine and the liver, which is the major source for plasma Sepp1. Little is known about the role of selenium and Sepp1 in inflammatory bowel disease (IBD), a condition of intermittent severe oxidative stress. However, its antioxidant activities suggest that Sepp1 dysfunction could contribute to IBD pathogenesis, particularly during progression to inflammatory neoplasia. In support of this concept, Sepp1 is downregulated in IBD and SNPs in Sepp1 have been associated with advanced adenoma risk. Mechanistically, selenium depletion results in stimulation of the Wnt pathway, which is essential to intestinal stem cell programs and pivotal to mucosal repair in IBD and is one of the first pathways activated in oncogenesis. We have published that selenium deficiency in mice treated with azoxymethane/dextran sodium sulfate, a standard protocol for inflammatory carcinogenesis, had increased mucosal injury and progression to colitis-associated dysplasia (CAD). Likewise, germline Sepp1-deficient mice; as well as mice mutant for redox or Se-rich domains, had increased tumor burden with major effects on proliferation, apoptosis and DNA damage. Abolishing liver-sourced Sepp1 did not phenocopy germline Sepp1 deficiency, providing the first evidence that local Sepp1 production was important for intestinal integrity. Furthermore, Sepp1-/- enteroids have increased stem cell features and hyperplasia. These data suggest that Sepp1 that is locally produced is a major mediator of selenium's effects on epithelial integrity. However, many important questions remain: 1) Does intestinal Sepp1 impact colonic epithelial injury and repair? 2) Does intestinal Sepp1 protect against oxidative stress, mucosal injury and CAD? 3) Which stem cell pathways are modified by Sepp1 in influencing tumorigenesis? 4) Does manipulation of Sepp1 expression influence the growth of established tumors? We hypothesize that intestinal Sepp1 alters the inflammatory microenvironment via clearance of reactive oxygen species thus affecting epithelial stem cell and differentiation programs. We propose to test this hypothesis by using a combination of genetically engineered mice, inducible expression systems, and a newly developed enteroid platform. Collectively, these experiments will allow us to elucidate the role of Sepp1 in mucosal integrity responses and its potential merit as a therapeutic target in IBD.

描述（由申请人提供）：硒蛋白P（Sepp 1）是一种主要的硒蛋白，对肠上皮细胞稳态的贡献尚不清楚。硒（Se）是一种必需的微量元素，以硒代半胱氨酸的形式掺入蛋白质中。即使在严重缺硒的情况下，大部分可用的硒也用于合成Sepp 1，突出了这种蛋白质的重要性。Sepp 1具有两个结构域：氨基氧化还原结构域和羧基富硒结构域. Sepp 1在许多组织中表达，包括肠和肝脏，这是血浆Sepp 1的主要来源。关于硒和Sepp 1在炎症性肠病（IBD）中的作用知之甚少，IBD是一种间歇性严重氧化应激的疾病。然而，其抗氧化活性表明Sepp 1功能障碍可能有助于IBD发病机制，特别是在炎症性肿瘤的进展过程中。为了支持这一概念，Sepp 1在IBD中下调，Sepp 1中的SNP与晚期腺瘤风险相关。从机制上讲，硒耗竭导致Wnt途径的刺激，这对肠道干细胞程序至关重要，对IBD中的粘膜修复至关重要，并且是肿瘤发生中激活的第一条途径之一。我们已经发表了用氧化偶氮甲烷/葡聚糖硫酸钠（炎性致癌作用的标准方案）治疗的小鼠中的硒缺乏会增加粘膜损伤并进展为结肠炎相关发育不良（CAD）。同样，生殖系Sepp 1缺陷小鼠;以及氧化还原或富硒结构域的小鼠突变体，增加了肿瘤负荷，对增殖，凋亡和DNA损伤有重大影响。废除肝脏来源的Sepp 1并没有表现出种系Sepp 1缺陷，这首次证明了局部Sepp 1的产生对于肠道完整性很重要。此外，Sepp 1-/-类肠细胞具有增加的干细胞特征和增生。这些数据表明，Sepp 1是本地产生的硒的上皮完整性的影响的主要介质。然而，许多重要的问题仍然存在：1）肠道Sepp 1是否影响结肠上皮损伤和修复？2)肠道Sepp 1是否能保护机体免受氧化应激、粘膜损伤和CAD的影响？3)Sepp 1在影响肿瘤发生中修饰了哪些干细胞通路？4)操纵Sepp 1表达是否会影响已建立的肿瘤的生长？我们假设肠道Sepp 1通过清除活性氧改变炎症微环境，从而影响上皮干细胞和分化程序。我们建议通过使用基因工程小鼠，诱导表达系统和新开发的肠平台的组合来测试这一假设。总的来说，这些实验将使我们能够阐明 Sepp 1在粘膜完整性反应中的作用及其作为IBD治疗靶点的潜在价值