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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.