The anti-inflammatory effects of CeO2 nanoparticles in SLE

描述(申请人提供)：系统性红斑狼疮(SLE)是一种典型的自身免疫性疾病，具有一系列不同的临床表现，其特征是产生针对细胞核成分的自身抗体。MRL/MPJ-Faslpr(MRL/LPR)小鼠发生类似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激活的免疫异常。在狼疮性肾炎中，免疫复合体沉积在肾脏中，引发活化的免疫细胞涌入，释放蛋白水解酶、炎症介质、细胞因子和活性氧物种(ROS)。除非进行治疗干预，否则MRL/LPR小鼠和人类的狼疮性肾炎会进展为终末期肾病(ESRD)。根据定义，ROS是在其最外层的电子壳层中包含未配对电子的原子。当由于正常新陈代谢或病理状态而在细胞内产生时，自由基可以从细胞大分子中剥离电子，使它们功能失调。纳米技术包括在原子尺度上操纵材料的过程，在纳米范围内的尺寸。先前的研究表明，纳米氧化铈具有优异的抗氧化性能，在生物系统中具有强大的、可再生的自由基清除剂的作用。这些再生的抗氧化剂性能部分是由于Ce原子的价结构与晶格结构中的固有缺陷结合在一起，这些缺陷在纳米尺度上被放大。我们的初步数据表明，氧化铈纳米颗粒凭借其清除自由基的能力，通过减少狼疮小鼠体内活性氧物种的产生来减少炎症反应。因此，我们推测氧化铈纳米颗粒在价态、氧缺陷和抗氧化性方面的独特结构将减少狼疮性肾炎中炎症介质的产生，从而可能成为狼疮性肾炎的一种新的炎症阻断机制。为了验证我们的假说，我们将利用以下特定目标来研究氧化铈纳米颗粒对狼疮小鼠的影响：特定目标1.验证纳米氧化铈降低狼疮和非狼疮小鼠腹膜巨噬细胞和系膜细胞炎症能力的假说。具体目的2.验证纳米氧化铈抑制狼疮小鼠T细胞过度兴奋状态的假说。基于我们的初步研究，我们相信，氧化铈纳米颗粒可能会为更有效地治疗狼疮等炎症性疾病提供一条新的“纳米药理学”途径。拟议的研究将阐明氧化铈作为狼疮治疗药物的作用，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。项目简介：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方法包括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原子尺度上操纵纳米范围内的细胞功能的能力。我们建议使用纳米氧化铈作为自由基清除剂，可以预防炎症，减少狼疮疾病，从而可能成为预防和治疗疾病的新的特异性治疗方法。

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.