Tissue-specific contribution of Selenoprotein P in colitis and oxidative damage

硒蛋白 P 在结肠炎和氧化损伤中的组织特异性作用

基本信息

批准号：
9269673
负责人：
Sarah Palmer Short
金额：
$ 5.3万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-07 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9269673
关键词：
Affect Antioxidants Area Azoxymethane Bone Marrow Buffers Carcinoma Cell physiology Cells Coculture Techniques Colitis Colon Colon Carcinoma Colorectal Cancer DNA Damage Development Disease Disease Progression Dysplasia Epidemiologic Studies Epithelial Epithelial Cells Epithelium Generations Genomics Gray unit of radiation dose Homeostasis Hyperplasia Immune In Situ Inflammation Inflammatory Inflammatory Bowel Diseases Injury Intestinal Intraepithelial Neoplasia Intestines Knockout Mice Liver Malignant Neoplasms Mediating Mediator of activation protein Modeling Mus Mutation Myelogenous Myeloid Cells Neoplasms Nutritional Oxidation-Reduction Oxidative Stress Patients Phenotype Play Polyps Population Production Proteins Protocols documentation Role Selenium Selenocysteine Severities Severity of illness Sodium Dextran Sulfate Source Stem cells Supplementation Testing Tissues Trace Elements Variant adduct cancer prevention cancer risk carcinogenesis cell behavior cell injury cell type cytokine cytotoxicity defined contribution in vivo in vivo Model inhibitor/antagonist intestinal epithelium intestinal homeostasis macrophage mouse model oxidant stress oxidative damage public health relevance research study response selenocysteine-tRNA selenoprotein stemness tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Selenium is a necessary trace element that is incorporated as selenocysteine into selenoproteins, such Selenoprotein P (SEPP1). Several epidemiological studies have inversely correlated nutritional selenium status and cancer risk, particularly in colon cancer. Because SEPP1 is the only selenoprotein to contain more than one selenocysteine, SEPP1 is hypothesized to supply various tissues with selenium to allow in situ generation of selenium containing proteins. However, SEPP1 also contains a redox domain and fulfills a generalized antioxidant function. Such activities suggest that SEPP1 could play a significant role in cancer prevention, and indeed SEPP1 message is downregulated in colorectal cancers. Furthermore, we have found that global SEPP1 reduction increases tumorigenesis in mice placed on a colitis associated carcinoma protocol. But how is SEPP1 mediating these changes in tumor formation? As the majority of SEPP1 is thought to be synthesized in the liver, we previously generated a liver- specific Sepp1 knock-out mouse. Surprisingly, loss of SEPP1 in the liver had no effect on colitis score or tumor formation, suggesting a local source of SEPP1 might modify or influence tumorigenesis. Two possible sources for this locally-derived SEPP1 include 1) intestinal epithelial cells and 2) infiltrating immune cells. Both cell types are known o produce SEPP1, but their separate contributions to inflammatory injury and cancer are yet unknown. Therefore, we will delete SEPP1 in both cell populations individually to define tissue-specific contributions of SEPP1 to inflammatory carcinogenesis. To determine how SEPP1 influences tumor formation, we will utilize a combination of in vivo and ex vivo approaches for both epithelial and myeloid cell populations. Using mouse models of colitis and dysplasia, intestinal enteroid and macrophage/enteroid co-culture, and bone marrow macrophage culture we will determine how tissue-specific SEPP1 affects intestinal homeostasis, intestinal injury, oxidative stress, and macrophage function, and how each function contributes to colitis and associated dysplasia. Interestingly, we have found that Sepp1 loss increases oxidative damage in ex vivo intestinal culture models, and colitis- associated carcinoma is characterized by increased oxidant stress. To specifically investigate the role of oxidative damage and its mechanistic contribution to the SEPP1 phenotype, we will utilize the compound salicylamine, an inhibitor of oxidative adducts, as well as redox-deficient SEPP1 variants. Together, these experiments will elucidate the roles of selenium and SEPP1 in colon disease and disease progression.

描述（由适用提供）：硒是一种必要的痕量元素，被掺入硒代半胱氨酸蛋白，例如硒蛋白P（SEPP1）。几项流行病学研究已呈负相关的营养硒状况和癌症风险，尤其是在结肠癌中。由于SEPP1是唯一含有多种硒代半胱氨酸的硒蛋白，因此SEPP1被认为可以用硒提供各种时机，以允许原位含有蛋白质的硒。但是，SEPP1还包含氧化还原域并实现广义抗氧化功能。这些活动表明，SEPP1可以在预防癌症中发挥重要作用，而SEPP1信息实际上在结直肠癌中被下调。此外，我们发现全球SEPP1减少会增加与结肠炎相关癌协议的小鼠的肿瘤发生。但是SEPP1如何介导肿瘤形成的这些变化？由于大多数SEPP1被认为是在肝脏中合成的，因此我们以前产生了肝脏特异性SEPP1敲除小鼠。令人惊讶的是，肝脏中SEPP1的损失对结肠炎评分或肿瘤的形成没有影响，这表明SEPP1的局部来源可能会改变或影响肿瘤发生。该局部衍生的SEPP1的两个可能来源包括1）肠上皮细胞和2）浸润的免疫球。两种细胞类型都是已知的O产生SEPP1，但是它们对炎症损伤和癌症的单独贡献尚不清楚。因此，我们将单独删除两个细胞种群中的SEPP1，以定义SEPP1对炎症性癌变的组织特异性贡献。为了确定SEPP1如何影响肿瘤的形成，我们将利用体内和体内方法的组合用于上皮细胞和髓样细胞群体。使用结肠炎和发育不良的小鼠模型，肠道内肠to和巨噬细胞/胚胎培养以及骨髓巨噬细胞培养，我们将确定组织特异性的SEPP1如何影响肠道稳态，肠道损伤，氧化应激，氧化应激，巨噬细胞和巨噬细胞功能，以及每个功能如何促进肠胃炎和相关的疾病炎。有趣的是，我们发现SEPP1损失会增加体内肠道培养模型中的氧化损伤，而结肠炎相关的癌的特征是氧化物胁迫增加。为了特别研究氧化损伤及其对SEPP1表型的机理贡献，我们将利用复合水杨胺，一种氧化加合物的抑制剂以及氧化还原缺陷的SEPP1变体。总之，这些实验将阐明硒和SEPP1在结肠疾病和疾病进展中的作用。