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

描述（由申请人提供）：当抗体以免疫复合物存款的形式在肾脏中沉积时，会引起许多常见的肾脏疾病。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需要透析或移植的终末期肾衰竭。目前的治疗是非特异性的， 有毒，并不总是有效的。对于抗体沉积在肾脏中如何诱导随后的慢性炎症的理解存在根本性的差距。 Toll样受体是细胞表面受体，通常用于诱导对病原体的免疫应答，并且在所有哺乳动物中都很保守。我们假设Toll样受体的内源性配体在肾小球中抗体沉积后释放，并且这种配体作为“危险信号”在肾小球中启动损伤性炎症反应。为了更好地了解内源性Toll样受体配体在免疫复合物肾小球肾炎发病过程中的作用，我们开发了一种独特的小鼠模型，该模型模拟了人类免疫复合物肾小球肾炎的许多特征。在使用该模型的初步研究中，我们发现了Toll样受体7（TLR7），一种由单链RNA激活的受体，在免疫复合物肾小球肾炎的发病机制中的重要作用。在目标1中，我们将确定受损肾小球中免疫刺激RNA的来源，并确定另一种RNA敏感受体Toll样受体3是否也在疾病发展中发挥作用。在目标2中，我们将鉴定负责感测内源性RNA的免疫细胞或肾细胞。由于TLR7参与可以激活几种不同的信号级联，在目标3中，我们将确定不同的TLR7诱导的级联在多大程度上调节疾病表型和疾病进展的速率。我们的长期目标是利用我们将获得的关于小鼠中致病性Toll样受体信号通路的详细知识来确定治疗人类免疫复合物疾病的合理靶标。

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.