Cellular Selenium Status and PGJ2 Metabolism

细胞硒状态和 PGJ2 代谢

基本信息

批准号：
9266394
负责人：
KUMBLE SANDEEP PRABHU
金额：
$ 32.26万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9266394
关键词：
Acute Adoptive Transfer Affect Anti-Inflammatory Agents Anti-inflammatory Arachidonic Acids Arginine Bacteria Cells Chemical Injury Chemicals Citrobacter rodentium Citrulline Clinical Colitis Data Diet Dietary Selenium Dinoprostone Disease Duodenum Eicosanoid Metabolism Pathway Eicosanoids Funding Gastrointestinal Injury Gastrointestinal tract structure Goals Health Helminths Human Immune Immune system Immunoglobulin Class Switching Infection Infiltration Inflammation Inflammatory Injury Intestines Learning Mediating Metabolic Pathway Metabolism Modeling Molecular Mus Nippostrongylus Nitric Oxide Nuclear Ornithine Oxidation-Reduction PPAR gamma Pathogenicity Pathway interactions Phenotype Play Production Property Prostaglandin D2 Prostaglandins Resolution Role Selenium Selenocysteine Shunt Device Small Intestines Sodium Dextran Sulfate T-Lymphocyte Testing Trace Elements Transfer RNA Urea Wound Healing base cytokine eicosanoid metabolism gastrointestinal gastrointestinal infection glutathione peroxidase intestinal homeostasis jejunum macrophage metabolome metabolomics pathogen protective effect protein function public health relevance response response to injury selenoprotein shunt pathway transcription factor

项目摘要

DESCRIPTION (provided by applicant): Understanding the molecular mechanisms that underlie the pro-resolving functions of selenoproteins (containing selenium (Se) as selenocysteine) may hold the key to alleviating diseases where insults to the gastrointestinal (GI) tract are commonly seen. Using three diverse models of gut injury exemplified by dextran sodium sulfate (DSS)-induced chemical injury, GI infection by the enteropathogenic bacterium, Citrobacter rodentium, or helminth Nippostrongylus brasiliensis, the ability of the gut immune system to resolve inflammation will be examined. Studies from the last cycle demonstrated the ability of Se to effectively shunt the arachidonic acid pathway of eicosanoid metabolism from pro-inflammatory prostaglandin E2 (PGE2) towards the anti-inflammatory 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) in macrophages. Such a metabolite "class switching" occurs as a result of redox changes by the way of selenoprotein-dependent differential modulation of transcription factors, nuclear factor (NF)-κB and peroxisome proliferator activated receptor (PPAR)-γ that impact many metabolic pathways, including the eicosanoid and L-arginine (L-Arg) pathway. As a result, selenoprotein expression was critical for polarizing pro-inflammatory M1 (Th1; classically-activated) macrophages towards an M2-like (Th2; alternatively activated) phenotype. Our studies suggest that changes in the metabolome are key to such a phenotypic switch towards reparative M2 macrophages that are endowed with anti-inflammatory and pro-resolving properties, which will be tested in three diverse models. Preliminary data suggest that selenoproteins are critical to efficiently resolve injury in all three models. Thus, our studies ar based on the overarching hypothesis that selenoprotein expression alters metabolic pathways to mitigate inflammation while promoting resolution following injury. The hypothesis will be tested using mice that lack selenoproteins in macrophages and T-cells: 1) to determine the role of selenoproteins on the pro-resolving functions of M2 macrophages following chemical injury; 2) to determine the role of selenoproteins in resolving inflammation following a Th2 mediated infection; and 3) to determine the pro-resolving functions of selenoproteins following a Th1/Th17 mediated infection. These studies will test if the pro-resolving properties of selenoproteins are dependent on the changes in the metabolome in three models of GI inflammation. The long-term goal of our studies is to understand the role of selenium in GI homeostasis is mediated through changes in the metabolism of immune cells.

描述（由申请人提供）：了解含硒蛋白（含有硒 (Se) 作为硒代半胱氨酸）的促分解功能的分子机制可能是缓解常见损害胃肠道 (GI) 的疾病的关键。三种不同的肠道损伤模型，例如右旋糖酐硫酸钠（DSS）-化学诱导的损伤，肠病原菌引起的胃肠道感染细菌、啮齿类柠檬酸杆菌或巴西圆线虫蠕虫，将检查肠道免疫系统解决炎症的能力，上一个周期的研究表明，硒能够有效地从促炎性前列腺素 E2 中分流花生四烯酸代谢途径。 (PGE2) 朝向抗炎 15-脱氧-Δ12,14-PGJ2 (15d-PGJ2)在巨噬细胞中，这种代谢物“类别转换”是通过转录因子、核因子 (NF)-κB 和过氧化物酶体增殖物激活受体 (PPAR)-γ 的硒蛋白依赖性差异调节方式发生氧化还原变化的结果，影响许多因素。代谢途径，包括类二十烷酸和 L-精氨酸 (L-Arg) 途径因此，硒蛋白表达对于极化促炎症 M1 (Th1；我们的研究表明，代谢组的变化是向具有抗炎和促消退特性的修复性 M2 巨噬细胞表型转变的关键。将在三种不同的模型中进行测试，初步数据表明，硒蛋白对于有效解决所有三种模型中的损伤至关重要。硒蛋白表达改变代谢途径以减轻炎症，同时促进损伤后的消退该假设将使用巨噬细胞和 T 细胞中缺乏硒蛋白的小鼠进行测试：1) 确定硒蛋白对化学处理后 M2 巨噬细胞的促消退功能的作用。损伤；2) 确定硒蛋白在解决 Th2 介导的感染后炎症中的作用；以及 3) 确定硒蛋白的促解决功能。这些研究将测试硒蛋白的促消退特性是否依赖于三种胃肠道炎症模型中代谢组的变化。硒在胃肠道稳态中的作用是通过免疫细胞代谢的变化来介导的。