This revised proposal describes a 5-year training program to enable the applicant to expand her scientific knowledge, advance her technical skills, and establish independence from her primary mentor. In addition to the primary mentor, the applicant has 3 co-mentors to help her achieve the goals of this proposal. The overall scientific objectives are to elucidate how adiponectin exerts its therapeutic benefits in systemic lupus erythematosus (SLE) and to determine whether elevated levels of endogenous retinaldehyde (Raid) in SLE may contribute to disease pathogenesis through inhibition of PPARg signaling. We have shown that the 3PARg agonist rosiglitazone ameliorates disease in two murine lupus models, MRL-lpr and gld.apoE. Further more, we generated MRL-lpr mice deficient in adiponectin and found that rosiglitazone has no therapeutic effect in these mice indicating that rosiglitazone exerts its beneficial effects primarily through induction of adiponectin. We hypothesize that this is mediated either by direct effects of adiponectin on specific adiponectin receptors and/or by adiponectin-mediated clearance of apoptotic material containing mmunostimulatory auto antigens. We also have preliminary data showing elevated plasma levels of Raid in lupus mice compared to wild type mice. Raid is a retinoic acid precursor that inhibits PPARg signaling. As PPARg strongly induces adiponectin expression, abnormal Raid accumulation may predispose to SLE by inhibiting PPARg signaling thereby decreasing adiponectin levels. To test our hypotheses, we will: 1) Determine adiponectin receptor expression and function on B cells and dendritic cells;2) Establish whether adiponectin can sequester biologically active lupus auto antigens, and whether deficiency of the adiponectin receptors AdipoR! or AdipoR2 exacerbates disease in the MRL-lpr lupus model;and 3) Measure the extent of Raid accumulation in various murine lupus models as well as in human patients with SLE, and evaluate the effects of Raid on the PPARg signaling pathway and on PPARg target genes. The proposed research will enhance our understanding of the mechanisms underlying the therapeutic benefit of adiponectin and PPARg signaling in SLE and may lead to novel therapeutic approaches for the human disease.
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