IgA nephropathy is the most common form of glomerulonephritis worldwide. Renal deposits of IgA immune complexes (IgA-IC) cause injury with remarkable similarities in the pathophysiologic features of human and experimental IgA nephropathy. This suggests that common genomic expression profiles account for the similar phenotypic changes of IgA nephropathy. Despite extensive studies, there is paucity of information about an effective therapeutic modality for IgA nephropathy. The mushroom Cordyceps sinensis extracts (CSE), a traditional Chinese medicine has been reported as a potential therapy for IgA nephropathy. Our long-term goal is to elucidate the molecular mechanisms underlying the pathogenesis of IgA nephropathy as a necessary pre-requisite to the development of rational therapeutic modalities. Based on clinical and experimental observations, the specific hypothesis is that IgA-IC activate Nuclear Factor-KappaB (NF-KappaB) signalinq pathway to generate a cascade of pro-inflammatory cytokines and growth factors consummating in glomerular sclerosis, interstitial fibrosis, and renal failure. A corollary of this postulate that Cordyceps (alternative medicine) inhibition of the NF-KappaB signalinq pathway will ameliorate IgA nephropathy.
The specific aims are to: 1. Determine the influence of Cordyceps sinensis extract on NF-KappaB signaling pathway activation and ability to halt progression of renal injury in IgA nephropathy. This will be achieved by correlating the level of NF-KappaB activation in transgenic luciferase reporter model with (i) IgA-IC deposition in immune and renal tissues, (ii) induction and progression of renal injury and (iii) comparing CSE effects with known anti-inflammatory and immunosuppressive NF-KappaB modulators (Prednisolone and Cyclosporine-A). 2. Identify pivotal genes in IgA nephropathy transcriptome profiles modulated by NF-KappaB signaling and in response to CSE, Prednisolone or Cyclosporine-A. This will be achieved by (i) comprehensive transcriptome analysis, (ii) correlation of tissue luciferase activity level (NF-KappaB activation) with transcripts intensity, and (iii) expression validation of identified informative genes. These studies will generate novel insights into molecular mechanisms underlying pathogenesis of IgA nephropathy and predict outcomes from safe traditional alternative medicine for prevention of renal failure.
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