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（由申请人提供）：硒蛋白 P (Sepp1)（一种主要的硒蛋白）对肠上皮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 Sepp1，凸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在包括肠和肝脏在内的许多组织中表达，这是血浆Sepp1的主要来源。关于硒和 Sepp1 在炎症性肠病 (IBD)（一种间歇性严重氧化应激疾病）中的作用知之甚少。然而，其抗氧化活性表明 Sepp1 功能障碍可能导致 IBD 发病机制，特别是在进展为炎性肿瘤期间。为了支持这一概念，Sepp1 在 IBD 中表达下调，并且 Sepp1 中的 SNP 与晚期腺瘤风险相关。从机制上讲，硒耗尽会刺激 Wnt 通路，该通路对于肠道干细胞程序至关重要，对于 IBD 粘膜修复至关重要，也是肿瘤发生过程中首先激活的通路之一。我们发表了用氧化偶氮甲烷/右旋糖酐硫酸钠（炎症性癌变的标准方案）治疗的小鼠缺硒会增加粘膜损伤并进展为结肠炎相关发育不良（CAD）。同样，种系 Sepp1 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、细胞凋亡和 DNA 损伤产生重大影响。消除肝脏来源的 Sepp1 并没有对种系 Sepp1 缺陷进行表型复制，这提供了第一个证据表明本地 Sepp1 的产生对于肠道完整性很重要。此外，Sepp1-/- Enteroids 增加了干细胞特征和增生。这些数据表明，本地产生的 Sepp1 是硒对上皮完整性影响的主要介质。然而，许多重要问题仍然存在：1）肠道Sepp1是否影响结肠上皮损伤和修复？ 2) 肠道 Sepp1 是否可以预防氧化应激、粘膜损伤和 CAD？ 3) Sepp1 修饰哪些干细胞途径影响肿瘤发生？ 4）Sepp1表达的操纵是否会影响已形成肿瘤的生长？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。我们建议通过结合使用基因工程小鼠、诱导表达系统和新开发的肠类平台来检验这一假设。总的来说，这些实验将使我们能够阐明 Sepp1 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。