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

免疫复合物肾炎中 Toll 样受体的内源性 RNA 配体

基本信息

批准号：
8721950
负责人：
Ramon G.B. Bonegio
金额：
$ 36.76万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8721950
关键词：
Address Adjuvant Antibodies Antigen-Antibody Complex Autoimmune Process Bone Marrow Carrier Proteins Cell Surface Receptors Cells Characteristics Chimera organism Chronic Complex Crescentic Glomerulonephritis Data Dendritic Cells Deposition Development Dialysis procedure Disease Disease Progression Enhancers Epithelial Cells Fc Receptor Future Gene Expression Profile Genetic Polymorphism Glomerulonephritis Goals Heating Human IgG1 Immune Immune Complex Diseases Immune Complex Glomerulonephritis Immune response Immunoglobulin A Immunoglobulin G Immunosuppression In Vitro Inflammation Inflammatory Response Injury Interferons Kidney Kidney Diseases Kidney Failure Kinetics Knockout Mice Knowledge Lead Ligands Light Lupus Nephritis Mammals Mediating Mediator of activation protein Mitogen-Activated Protein Kinases Modeling Mus NFAB complex Nephritis Nephrotoxic Nuclear Outcome Pathogenesis Pathologic Pathology Pathway interactions Permeability Phase Play Predisposition Proteinuria RNA RNA Binding Receptor Cell Receptor Signaling Research Residual state Role Serum Severities Sheep Signal Pathway Signal Transduction Source Staging TLR3 gene Testing Therapeutic Time Toll-like receptors Transplantation activating transcription factor base disease phenotype disorder control expectation extracellular glomerular basement membrane human TLR3 protein human TLR7 protein human disease in vitro Assay inhibitor/antagonist injured kidney cell macrophage mesangial cell mouse model neutrophil new therapeutic target novel outcome forecast pathogen protective effect receptor

项目摘要

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.

描述（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中引起的。由此产生的肾脏炎症或肾小球肾炎通常具有破坏性，并随着时间的推移进展至需要透析或移植的终末期肾衰竭。目前的治疗方法没有特异性，有毒且并不总是有效。对于抗体在肾脏中的沉积如何诱发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，通常起到诱导对病原体的免疫反应的作用，并且在所有哺乳动物中都得到很好的保守。我们假设 Toll 样受体的内源性配体在抗体沉积在肾小球中后释放，并且此类配体充当“危险信号”，在肾小球中引发损伤性炎症反应。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机制中的作用，我们开发了一种独特的小鼠模型，模仿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性 RNA 的来源，并确定另一种 RNA 传感受体 Toll 样受体 3 是否也在疾病发展中发挥作用。在目标 2 中，我们将识别负责感知内源 RNA 的免疫细胞或肾细胞。由于 TLR7 参与可能激活几种不同的信号级联，因此在目标 3 中，我们将确定不同 TLR7 诱导的级联在多大程度上调节疾病表型和疾病进展速率。我们的长期目标是利用我们将获得的关于小鼠致病性 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。