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. ? ? ?
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