The anti-inflammatory effects of CeO2 nanoparticles in SLE

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种原型自身免疫性疾病，具有多种临床表现，其特征在于产生针对细胞核组分的自身抗体。MRL/MPJ-Faslpr（MRL/lpr）小鼠发生类似于人类疾病的狼疮性肾炎，包括影响T细胞和B细胞耐受机制和巨噬细胞活化的免疫异常。在狼疮性肾炎中，免疫复合物沉积在肾脏中，触发释放蛋白水解酶、炎症介质、细胞因子和活性氧（ROS）的活化免疫细胞的流入。除非采取治疗干预措施，否则MRL/lpr小鼠和人类的狼疮性肾炎会发展为终末期肾病（ESRD）。根据定义，ROS是在其最外层电子中含有未成对电子的原子。当作为正常代谢或病理状态的结果在细胞内产生时，自由基可以从细胞大分子中剥离电子并使它们功能失调。纳米技术包括在原子尺度上以纳米范围的尺寸操纵材料的过程。先前的研究表明，氧化铈纳米颗粒具有优异的抗氧化性能，并在生物系统中作为有效的再生自由基清除剂。这些再生抗氧化性能部分是由于铈原子的价态结构与晶格结构中的固有缺陷相结合，这些缺陷在纳米尺度上被放大。我们的初步数据表明，氧化铈纳米粒子，凭借其自由基清除能力，减少狼疮小鼠的活性氧产生减少炎症反应。因此，我们假设氧化铈纳米颗粒的独特结构，相对于价态，氧缺陷和抗氧化性能将减少狼疮肾炎中炎症介质的产生，从而可能作为一种新的机制，阻断狼疮肾炎炎症。为了验证我们的假设，我们将利用以下特定目的研究氧化铈纳米颗粒在狼疮小鼠中的作用：特定目的1。测试氧化铈纳米颗粒降低狼疮和非狼疮小鼠腹腔巨噬细胞和系膜细胞炎症能力的假设。具体目标2。测试氧化铈纳米颗粒抑制狼疮小鼠T细胞过度兴奋状态的假设。基于我们的初步研究，我们认为氧化铈纳米颗粒可能为更有效地治疗炎症性疾病（如狼疮）提供一种新的“纳米药理学”途径。拟议的研究将描绘氧化铈作为狼疮治疗剂的作用，并为对基础科学研究感兴趣的本科生和研究生提供宝贵的培训机会。系统性红斑狼疮是一种自身免疫性疾病，几乎可以影响身体的每一个组织。目前批准的狼疮治疗涉及非特异性免疫抑制剂。纳米技术的最新进展为我们提供了在纳米范围内的原子尺度上操纵细胞功能的能力。我们建议使用氧化铈纳米颗粒作为自由基清除剂将预防炎症和减少狼疮疾病，因此可能作为预防和治疗疾病的新的特异性疗法。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with a diverse array of clinical manifestations characterized by the production of autoantibodies to components of the cell nucleus. MRL/MPJ- Faslpr (MRL/lpr) mice develop lupus nephritis similar to human disease including immune abnormalities affecting T cell and B cell tolerance mechanisms and macrophage activation. In lupus nephritis, immune complexes become deposited in the kidney triggering an influx of activated immune cells that release proteolytic enzymes, inflammatory mediators, cytokines, and reactive oxygen species (ROS). Unless a therapeutic intervention is instituted, lupus nephritis in MRL/lpr mice and in humans progresses to end stage renal disease (ESRD). By definition, ROS are atoms which contain an unpaired electron in its outermost shell of electrons. When generated intracellularly as a consequence of normal metabolism or pathological states, free radicals can strip electrons from cellular macromolecules and render them dysfunctional. Nanotechnology encompasses the process of manipulating materials on an atomic scale, at dimensions in the nanometer range. Previous studies have demonstrated that cerium oxide nanoparticles possess excellent antioxidant properties and act as potent, regenerative free radical scavengers in biological systems. These regenerative antioxidant properties are due, in part, to the valence structure of the cerium atom combined with inherent defects in the crystal lattice structure, which are magnified at the nano-scale. Our preliminary data suggest that cerium oxide nanoparticles, by virtue of their free radical scavenging capacity, reduce the inflammatory response by decreasing reactive oxygen species production in lupus mice. We therefore hypothesize that the unique structure of cerium oxide nanoparticles, with respect to valence, oxygen defects, and antioxidant properties will decrease inflammatory mediator production in lupus nephritis and thus may serve as a novel mechanism for blocking inflammation in lupus nephritis. To test our hypothesis we will investigate the effects of cerium oxide nanoparticles in lupus mice utilizing the following specific aims: Specific Aim 1. Test the hypothesis that cerium oxide nanoparticles decrease the inflammatory capacity of peritoneal macrophage and mesangial cells from lupus and non-lupus mice. Specific Aim 2. Test the hypothesis that cerium oxide nanoparticles inhibit the hyperexcitable state of T-cells from lupus mice. Based on our pilot studies, we believe that cerium oxide nanoparticles may provide a new avenue of "nanopharmacology" for more effective treatment of inflammatory disorders such as lupus. The proposed studies will delineate the role of cerium oxide as a therapeutic for lupus and provide valuable training opportunities to undergraduate and graduate students interested in basic science research. PROJECT NARRATIVE: Systemic lupus erythematosus is an autoimmune disease that can affect nearly every tissue of the body. Currently approved treatments for lupus involve non-specific immunosuppressive agents. The recent advances in nanotechnology provide us the ability to manipulate cellular function on an atomic scale at dimension in the nanometer range. We propose the use of cerium oxide nanoparticles as free radical scavengers will prevent inflammation and decrease lupus disease and thus may serve as new specific therapy to prevent and treat disease.