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Molecular Basis of Pathogenicity of IgA1-containing Immune Complexes

含 IgA1 的免疫复合物致病性的分子基础

基本信息

批准号：
8504854
负责人：
JAN NOVAK
金额：
$ 21.98万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8504854
关键词：
Animal Model Antibodies Antigen-Antibody Complex Autoantibodies Binding Biological Assay Cell Line Cell Proliferation Cells Characteristics Chronic Clinical Clinical Investigator Clinical Research Complex Data Deposition Detection Development Disease Dose End stage renal failure Engineering Event Extracellular Matrix Proteins Frequencies Functional disorder Galactose Glomerulonephritis Heterogeneity Histologic Human IgA1 Immune Immunoglobulin A Immunoglobulin G Immunoglobulin Variable Region In Vitro Integrins Kidney Kidney Diseases Kidney Failure Lead Light Mediating Modeling Molecular Molecular Analysis Molecular Profiling PDGFRB gene Pathogenesis Pathogenicity Pathway interactions Patients Peptides Pharmaceutical Preparations Phenotype Phosphotransferases Polysaccharides Prevention Prognostic Marker Proliferating Protein Kinase Protein Kinase Inhibitors Protein Tyrosine Kinase Proteins Proteomics Protocols documentation Recombinant Antibody Role Serum Signal Pathway Signal Transduction Small Interfering RNA Staging Testing Therapeutic Time Tyrosine Phosphorylation Vascular Endothelial Growth Factor Receptor base clinically significant cytokine disorder control glycosylation in vivo in vivo Model inhibitor/antagonist innovation insight kidney cell kinase inhibitor knock-down mesangial cell molecular mass mouse model new therapeutic target non-invasive monitor novel novel therapeutics outcome forecast prevent profilin protein kinase inhibitor public health relevance receptor research study response small molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): IgA nephropathy (IgAN) is the most common primary glomerulonephritis and an important cause of end-stage kidney failure. It is a mesangioproliferative glomerulonephritis defined by IgA1 mesangial deposits. Although it has been speculated for some time that the pathogenesis of IgAN is driven by deposition of circulating immune complexes (IC), this has been difficult to prove due to the lack of animal models of IgAN. Our development of new protocols that permit formation of engineered IC in vitro and establishment of a passive mouse model of IgAN provide an unprecedented opportunity to elucidate the pathophysiology of IgAN and identify potential therapeutic targets. In IgAN, a fraction of circulating IgA1 has galactose-deficient O-glycans (Gd-IgA1) and is present in circulating IC bound by glycan-specific autoantibodies. We now have characterized Gd-IgA1 and the anti-Gd-IgA1 autoantibodies that are present in these IC and used targeted proteomic approaches to both define the serum factors that associate with these IC and may contribute to their pathogenic effects and to identify the mesangial-cell receptors for the ICs. Rational extension of these studies required analysis of the molecular effects of these pathogenic IgAN ICs on the signaling events that lead to mesangial-cell activation. Global kinase-activity profilin using an innovative peptide substrate microarray platform of human mesangial cells stimulated with Gd-IgA1 IC identified robust tyrosine kinase activity as a major player in IC-induced signaling in three predominant pathways. Similar results were obtained with native and engineered ICs. The mesangial-cell responses after stimulation with these IC were typical of IgAN but differed from those obtained by using IC lacking all of the components in pathogenic ICs. An association with pathogenesis was demonstrated using protein-kinase inhibitors, which confirmed that one of the inhibitors completely blocked IC- mediated mesangial cell proliferation in vitro as well as in vivo in the passive mouse model of IgAN. These data suggest the hypothesis that Gd-IgA1-containing ICs represent a key hit in the pathogenesis of IgAN by activating mesangial cells through specific signaling pathways; the corollary is that this IC-drive signaling in mesangial cells can be blocked by small-molecular-mass inhibitors of protein kinases and thus represents a feasible therapeutic target(s). The team of basic and clinical investigators that has developed the powerful proteomic, kinomic, and cellular approaches used to generate the preliminary data will now test this hypothesis by: 1) Defining the characteristics of Gd-IgA1-containing ICs from sera of patients with IgAN that activate human mesangial cells; 2) Characterizing the signaling pathways activated by Gd-IgA1-containing ICs in mesangial cells; and 3) Determining the efficacy of small-molecular-mass inhibitors of key protein kinases on mesangial cell activation in vivo using the animal model of IgAN. Relevance: The results will shed light on the pathogenesis of IgAN and identify therapeutic targets for disease-specific treatment of IgAN as well as potential response/prognostic biomarkers.

描述（由申请人提供）：IgA肾病（IgAN）是最常见的原发性肾小球肾炎，是终末期肾衰竭的重要原因。这是一种由IgA1系膜沉积物定义的系膜增生性肾小球肾炎。虽然一段时间以来人们一直推测IgAN的发病机制是由循环免疫复合物（IC）的沉积驱动的，但由于缺乏IgAN的动物模型，这一点很难得到证实。我们开发的新方案允许在体外形成工程IC，并建立IgAN的被动小鼠模型，为阐明IgAN的病理生理学和确定潜在的治疗靶点提供了前所未有的机会。在