Selenium in gastrointestinal inflammatory diseases

硒在胃肠道炎症疾病中的作用

• 批准号: 8694743
• 负责人: Christopher S. Williams
• 金额: $ 39.09万
• 依托单位: VANDERBILT UNIVERSITY
• 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/8694743
• 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; Epidemiologic Studies; Epithelial; Epithelium; F2-Isoprostanes; Functional disorder; Genetically Engineered Mouse; Growth; Homeostasis; Hyperplasia; Image; Implant; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Interleukin-10; Intestines; Kinetics; Knowledge; Liver; MC38; Malignant Neoplasms; Mediator of activation protein; Metabolism; Modeling; Molecular; Molecular Analysis; Mus; Mutant Strains Mice; Mutation; Neoplasms; Nutritional; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Phenocopy; 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; gastrointestinal; injury and repair; intestinal epithelium; macrophage; polyposis; programs; public health relevance; repaired; research study; 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(申请人提供)：硒蛋白P(Sepp1)，一种主要的硒蛋白，对肠上皮内稳态的贡献尚不清楚。硒(Se)是一种必需的微量元素，以硒半胱氨酸的形式存在于蛋白质中。即使在严重缺硒的情况下，大部分可利用的硒也被用于合成Sepp1，这突显了这种蛋白质的重要性。Sepp1有两个结构域：氨基氧化还原结构域和羧基富硒结构域。Sepp1在许多组织中表达，包括肠和肝脏，这是血浆Sepp1的主要来源。人们对硒和Sepp1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状态。然而，其抗氧化活性表明Sepp1功能障碍可能与IBD的发病机制有关，特别是在发展为炎性肿瘤的过程中。支持这一概念的是，Sepp1在IBD中表达下调，而Sepp1中的SNPs与晚期腺瘤风险相关。从机制上讲，缺硒导致Wnt途径的刺激，Wnt途径是肠道干细胞计划的关键，也是IBD粘膜修复的关键，也是肿瘤发生中最早激活的途径之一。我们已经发表了用偶氮甲烷/葡聚糖硫酸钠治疗小鼠的硒缺乏，这是炎症性癌变的标准方案，增加了粘膜损伤并进展为结肠炎相关性异型增生(CAD)。同样，种系Sepp1缺陷小鼠，以及氧化还原或富硒结构域突变的小鼠，都增加了肿瘤负担，主要影响了增殖、凋亡和DNA损伤。废除肝脏来源的Sepp1不会导致种系Sepp1缺乏，这提供了第一个证据，表明局部Sepp1的产生对肠道完整性很重要。此外，Sepp1-/-肠样体增加了干细胞的特性和增殖。这些数据表明，当地生产的Sepp1是硒对上皮完整性影响的主要中介。然而，许多重要的问题仍然存在：1)肠Sepp1是否影响结肠上皮损伤和修复？2)肠Sepp1是否对氧化应激、粘膜损伤和CAD具有保护作用？3)Sepp1在影响肿瘤发生中修饰了哪些干细胞途径？4)Sepp1表达的操作是否影响已建立的肿瘤的生长？我们假设，肠道Sepp1通过清除活性氧来改变炎症微环境，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、可诱导表达系统和新开发的肠样平台的组合来验证这一假设。总而言之，这些实验将使我们能够阐明 Sepp1在黏膜完整性反应中的作用及其作为IBD治疗靶点的潜在价值。