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）是一种必不可少的痕量元素，它被掺入蛋白质为硒代半胱氨酸。即使在严重硒缺乏症的条件下，大多数可用的硒也用于合成SEPP1，突出了该蛋白质的重要​​性。 SEPP1有两个领域：一个氨基氧化还原和羧基Se-Rich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）中的作用，这是间歇性严重氧化应激的疾病。但是，其抗氧化活性表明SEPP1功能障碍可能有助于IBD发病机理，尤其是在炎症性肿瘤的过程中。为了支持这个概念，SEPP1在IBD中被下调，SEPP1中的SNP与晚期腺瘤风险有关。从机械上讲，硒的耗竭会导致Wnt途径的刺激，这对于肠道干细胞程序至关重要，并且对IBD中的粘膜修复至关重要，并且是肿瘤发生中最早激活的途径之一。我们已经发表了，用硫酸苯甲烷/葡萄糖钠硫酸钠治疗的小鼠的硒缺乏症是炎性癌变的标准方案，其粘膜损伤增加并进展到与结肠炎相关的发育不良（CAD）。同样，种系SEPP1缺陷小鼠；以及用于氧化还原或富含SE的域的小鼠突变体增加了肿瘤负担，对增殖，凋亡和DNA损伤产生重大影响。废除肝脏的SEPP1并未表现性生殖线SEPP1缺乏症，这提供了第一个证据，表明局部SEPP1产生对肠道完整性很重要。此外，sepp1 - / - 肠道素具有增加的干细胞特征和增生。这些数据表明，本地生产的SEPP1是硒对上皮完整性影响的主要中介。但是，仍然存在许多重要的问题：1）肠SEPP1是否会影响结肠上皮损伤和修复？ 2）肠SEPP1是否可以防止氧化应激，粘膜损伤和CAD？ 3）在影响肿瘤发生时SEPP1修饰哪些干细胞途径？ 4）操纵SEPP1表达是否会影响已建立肿瘤的生长？我们假设肠道SEPP1通过清除活性氧气改变了炎症微环境，从而影响上皮干细胞和分化程序。我们建议通过结合基因工程小鼠，诱导表达系统和新开发的肠托体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 粘膜完整性反应中的SEPP1及其作为IBD治疗目标的潜在优点。