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

描述(申请人提供)：一些常见的肾脏疾病是由于抗体以免疫复合体的形式沉积在肾脏中而引起的。由此产生的肾炎或肾小球肾炎通常是破坏性的，并随着时间的推移而进展到需要透析或移植的终末期肾功能衰竭。目前的治疗方法是非特异性的， 有毒且并不总是有效。在了解抗体在肾脏中沉积如何导致随后的慢性炎症方面，存在着根本的差距。Toll样受体是一种细胞表面受体，通常功能是诱导对病原体的免疫反应，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是在抗体沉积在肾小球后释放的，这种配体是一个“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体肾炎发病机制中的作用，我们建立了一种独特的小鼠模型，该模型模仿了人类免疫复合体肾炎的许多特征。在使用该模型的初步研究中，我们发现Toll样受体7(TLR7)在免疫复合型肾小球肾炎的发病机制中起着重要作用。在目标1中，我们将确定受损肾小球中免疫刺激核糖核酸的来源(S)，并确定另一种核糖核酸感应受体Toll样受体3是否也在疾病的发生发展中发挥作用。在目标2中，我们将识别负责感知内源性RNA的免疫细胞或肾脏细胞。由于TLR7参与可能激活几个不同的信号级联反应，在目标3中，我们将确定TLR7诱导的不同级联反应在多大程度上调节疾病表型和疾病进展速度。我们的长期目标是利用我们将获得的关于小鼠致病Toll样受体信号通路的详细知识来确定治疗人类免疫复合体疾病的合理靶点。 公共卫生相关性：免疫复合体引起的肾脏疾病是世界范围内肾炎的最常见原因，也是美国肾衰竭的常见原因。这项拟议的研究将描绘内源性Toll样受体信号通路，这些通路是肾脏中抗体沉积后破坏性肾小球炎症和蛋白尿的关键介质。对这些致病途径的基础知识将为未来人类自身免疫性肾病的治疗方法的发展提供合理的靶点，并定义指示预后的转录图谱。

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. PUBLIC HEALTH RELEVANCE: Immune complex-induced kidney diseases are the commonest cause of nephritis world-wide and a common cause of kidney failure in the USA. The proposed research will delineate the endogenous Toll-like receptor signaling pathways that are key mediators of destructive glomerular inflammation and proteinuria following antibody deposition in the kidney. Fundamental knowledge of these pathogenic pathways will provide rational targets for the development of future therapeutics for autoimmune kidney disease in human beings, as well as define transcriptional profiles indicative of prognosis.