Cellular Selenium Status and PGJ2 Metabolism

 描述(由申请人提供)：了解硒蛋白(含硒(Se)作为硒半胱氨酸)促进分解功能的分子机制可能是缓解常见胃肠道(GI)损伤的疾病的关键。使用三种不同的肠道损伤模型，例如葡聚糖硫酸钠(DSS)诱导的化学损伤、肠道致病细菌、轮状柠檬酸杆菌或巴西尼波斯特菌蠕虫的GI感染，将检测肠道免疫系统消炎的能力。上一个周期的研究表明，在巨噬细胞中，硒能够有效地将二十烷类代谢的花生四烯酸途径从促炎症的前列腺素E_2(PGE_2)分流到抗炎的15-脱氧前列腺素12，14-前列腺素J_2(15d-_2)。这种代谢产物的“类别转换”是通过硒蛋白依赖的差异调节转录因子、核因子-B和过氧化物酶体增殖物激活受体-的方式发生氧化还原变化的结果，这些转录因子影响许多代谢途径，包括二十烷类化合物和L-精氨酸(L-精氨酸)途径。因此，硒蛋白的表达对于促进炎症的M1(Th1；经典激活的)巨噬细胞向M2样(Th2；交替激活)表型的分化至关重要。我们的研究表明，代谢组的变化是这种表型转换到具有抗炎和促分解特性的修复性M2巨噬细胞的关键，这将在三个不同的模型中进行测试。初步数据表明，硒蛋白在所有三种模型中都是有效解决损伤的关键。因此，我们的研究是基于一个重要的假设，即硒蛋白的表达改变代谢途径，以减轻炎症，同时促进损伤后的分解。这一假说将通过在巨噬细胞和T细胞中缺乏硒蛋白的小鼠进行验证：1)确定硒蛋白在化学损伤后M2巨噬细胞的促分解功能中的作用；2)确定硒蛋白在Th2介导的感染后化解炎症中的作用；以及3)确定Th1/Th17介导的感染后硒蛋白的促分解功能。这些研究将测试硒蛋白的促分解特性是否依赖于三种胃肠道炎症模型中代谢物的变化。我们研究的长期目标是了解硒在胃肠道动态平衡中的作用是通过改变免疫细胞的代谢来调节的。

 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-12,14-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)-B and peroxisome proliferator activated receptor (PPAR)-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.