Endogenous RNA Ligands For Toll-like Receptors In Immune-Complex Nephritis

描述（由申请人提供）：许多常见的肾脏疾病是由免疫复合物形式的抗体沉积在肾脏引起的。由此产生的肾脏炎症或肾小球肾炎通常是破坏性的，并随着时间的推移发展为终末期肾衰竭，需要透析或移植。目前的治疗方法是非特异性的，

DESCRIPTION (provided by applicant): A number of common kidney diseases are cause when antibodies in the form of immune complexes deposit in the kidney. The resulting kidney inflammation or glomerulonephritis is often destructive and progresses over time to end-stage kidney failure that requires dialysis or transplantation. Current therapies are non-specific, toxic and not always effective. There is a fundamental gap in the understanding of how antibody deposition in the kidney induces subsequent chronic inflammation. Toll-like receptors are cell surface receptors that usually function to induce immune responses to pathogens and are well conserved in all mammals. We hypothesize that endogenous ligands for Toll-like receptors are released following antibody deposition in the glomerulus and that such ligands serve as a "danger signal" that initiates injurious inflammatory responses in the glomerulus. In order to better understand the role of endogenous Toll-like receptor ligands during the pathogenesis of immune complex glomerulonephritis, we have developed a unique mouse model that mimics many of the characteristic features of immune complex glomerulonephritis in humans. In preliminary studies using this model, we discovered an important role of Toll-like receptor 7 (TLR7), a receptor activated by single stranded RNA, in the pathogenesis of immune complex glomerulonephritis. In aim 1, we will define the source(s) of immunostimulatory RNA in the injured glomerulus and determine if Toll-like receptor 3, another RNA-sensing receptor, also plays a role in disease development. In aim 2, we will identify the immune or kidney cells responsible for sensing endogenous RNA. As TLR7 engagement may activate several distinct signaling cascades, in aim 3 we will determine to what extent the different TLR7-induced cascades regulate disease phenotype and the rate of disease progression. Our long term goal is to use the detailed knowledge tht we will gain about pathogenic Toll-like receptor signaling pathways in mice to identify rational targets to treat immune complex disease in humans.