Targeting renal inflammatory pathways of SLE nephritis in mouse and man

Feinstein Institute For Medical Research, Manhasset NY

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Abstract

DESCRIPTION (provided by applicant): This proposal is a collaborative venture from the Davidson and Kretzler laboratories that reflects a set of converging experiments based on gene discovery in human and murine SLE nephritis, and a set of functional studies in mice based on hypotheses generated as a result of these studies. The proposal is based on the central hypothesis that molecular markers of SLE nephritis progression pathways can serve as predictors of outcome and therapeutic response. Using a unique model of remission induction of murine SLE nephritis we have identified two main physiologic pathways are associated disease onset and remission. These are: 1) activation of the renal endothelium and 2) activation of renal macrophages and dendritic cells with production of pro-inflammatory cytokines. Part of the signature is shared with other progressive murine renal diseases and both signatures overlap significantly with those found in human SLE renal biopsies. We have further discovered that activation of resident renal macrophages is a hallmark of onset of clinical nephritis in several disparate murine SLE models and is associated with upregulation of ITGAM, a gene that has recently been found to confer SLE risk. The current proposal focuses on the activation pathways of macrophages/dendritic cells in the kidneys with a view to identifying key pathways that could be targeted therapeutically. We will first determine the phenotype and origins of activated macrophages/monocytes in murine lupus kidneys and whether their precursors can be found in the peripheral blood. We will then characterize the function of activated macrophages and dendritic cells in the kidneys and urine sediment. We will use a combination of immuno- histochemistry, flow cytometry, functional studies and gene expression profiling to identify genes that are putative severity/prognostic markers or that are biomarkers for disease onset, remission and relapse. Parallel studies in human SLE renal biopsies and urinary cell pellets will allow us to identify pathways that can further be explored functionally in the murine models. At the same time candidate genes identified in the murine models will be evaluated in the human samples using a costume array qRT-PCR approach. More sophisticated systems based analysis of the human and murine data sets will help identify key signal transduction and transcriptional pathways that can be targeted therapeutically. Our studies allow us to make maximal use of large data sets to hone in on pathways that are likely to be shared among SLE patients. In addition we plan to build our consortium for standardized state-of-the-art tissue procurement and banking and to make data available through sophisticated web based tools for sharing with other investigators. PUBLIC HEALTH RELEVANCE: Kidney disease is a significant cause of death and disability in patients with SLE. Current treatments have insufficient efficacy and high toxicity. Because SLE patients differ from each other with respect to the patterns of kidney disease we will use several mouse models of SLE nephritis to understand more about the mechanisms for kidney inflammation and remission in different types of kidney disease and use the data obtained to probe information obtained from human SLE kidney biopsies. We will perform gene discovery experiments to identify novel patterns of gene expression that are associated with the various stages of kidney disease and with responses to treatment. Our studies should help us identify new pathogenetic disease mechanisms, to find novel targets for therapeutic intervention and to identify robust biomarkers that will help predict outcomes and responses to therapy.