Novel Receptor-Ligand Interactions in Glomerulonephritis

肾小球肾炎中新型受体-配体相互作用

基本信息

批准号：
8107756
负责人：
MARY H. FOSTER
金额：
$ 38.57万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8107756
关键词：
ANCA vasculitis Abbreviations Address Affect Amino Acid Motifs Amino Acids Antibodies Antigen Targeting Antigen-Presenting Cells Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Lymphocytes Binding Sites C-terminal Cells Chronic Kidney Failure Collaborations Collagen Collagen Diseases Complementarity Determining Region III Complementarity Determining Regions Computer Simulation Development Diagnostic Dialysis procedure Disease Drug Design Drug Industry Drug or chemical Tissue Distribution Engraftment Epitopes Genes Genetic Glomerulonephritis Goals Goodpasture Syndrome Hematopoietic Hematopoietic stem cells Human Immune Immune system Immunity In Vitro Intervention Kidney Kidney Diseases Ligands Light Link Lymphocyte Mass Spectrum Analysis Mediating Modeling Molecular Nephritis Onset of illness Organ Transplantation Pathogenesis Patients Peripheral Blood Lymphocyte Plant Roots Population Preclinical Testing Proteins Proteomics Reagent Regulation Research Research Design Rheumatoid Arthritis Rheumatologic Disorder Structure Subgroup System Technology Testing Therapeutic Transgenes Transgenic Organisms Transplantation antigen binding base clinically relevant complementarity-determining region 3 density glomerular basement membrane graft vs host disease in vivo in vivo Model innovation insight mimicry mouse model novel novel diagnostics novel therapeutic intervention patient population receptor reconstitution research study tool type IV collagen alpha3 chain validation studies

项目摘要

DESCRIPTION (provided by applicant): Anti-GBM nephritis, the prototypic autoimmune nephritis for which the kidney target antigen is well characterized, is a key system for discovery involving human kidney disease pathogenesis. Nephritogenic epitopes reside on alpha3 (IV) NC1 collagen within the glomerular basement membrane. Compelling recent discoveries indicate the existence of a crossreactive and previously unsuspected additional self-antigen involved in disease pathogenesis, as well as immunological links between diverse anti-collagen diseases. These findings indicate remarkable complexity in autoimmune disease regulation, the elucidation of which will provide new insights into disease onset, suppression, and arrest. The goals of this proposal are to identify this second antigen and the molecular basis of novel receptor-ligand interactions, and to explore their engagement in human autoimmunity and disease pathogenesis in vivo. This effort relies on cutting edge but validated technologies and cross-disciplinary collaborations. Specific Aim 1 will use state-of-the- art and complementary proteomics approaches to identify the unknown second antigen that engages and regulates pathogenic reactivity to alpha3(IV)NC1 collagen. Specific Aim 2 will use innovative computational prediction modeling to determine receptor-ligand structure, both to further inform Aim 1 and to provide new insight into potential environmental disease precipitants and overlapping autoimmune regulatory circuits. Specific Aim 3 will develop a humanized model to examine autoimmune responses in vivo in the context of a human immune system, using the NOD-scid-gamma strain for enhanced engraftment of hematopoietic cells. The model will also generate unique human immune reagents and tools, with the ultimate goal of providing a platform for preclinical testing to validate research findings and to test immune modulating interventions in vivo. PUBLIC HEALTH RELEVANCE: Autoimmunity affects an estimated 7% of the U.S. population and worldwide underlies most immune nephritis, a leading cause of chronic kidney disease affecting native and transplanted organs. This proposal examines new paradigms that emerged from the study of anti-GBM nephritis, the prototypic autoimmune nephritis for which the human kidney target antigen, alpha3(IV)NC1 collagen, is well characterized. Anti- GBM nephritis thus is a key system for discovery involving human kidney disease pathogenesis and immune regulatory networks. Moreover, anti-GBM autoimmunity contributes to disease in ANCA vasculitis, can be induced by immune modulating mAb therapies, and shares genetic and immunological links with anti-collagen II autoimmunity and rheumatoid arthritis. Thus the proposed studies, designed to find the root cause of these diseases, are anticipated to have broad clinical relevance. Novel insights and new tools can be applied to a large patient population to advance new diagnostic and therapeutic approaches!

描述（由申请人提供）：抗GBM肾炎是一种原型自身免疫性肾炎，其肾脏靶抗原已被充分表征，是涉及人类肾脏疾病发病机制的发现的关键系统。肾炎性表位位于肾小球基底膜内的 α3 (IV) NC1 胶原蛋白上。最近令人信服的发现表明，存在交叉反应性且先前未曾怀疑的额外自身抗原参与疾病发病机制，以及不同抗胶原疾病之间的免疫学联系。这些发现表明自身免疫性疾病调节的显着复杂性，对其的阐明将为疾病的发作、抑制和阻止提供新的见解。该提案的目标是鉴定第二种抗原和新型受体-配体相互作用的分子基础，并探索它们在体内人类自身免疫和疾病发病机制中的作用。这项工作依赖于尖端但经过验证的技术和跨学科合作。具体目标 1 将使用最先进的补充蛋白质组学方法来识别未知的第二抗原，该抗原参与并调节对 alpha3(IV)NC1 胶原蛋白的致病反应。具体目标 2 将使用创新的计算预测模型来确定受体-配体结构，既可以进一步为目标 1 提供信息，又可以提供对潜在环境疾病诱因和重叠自身免疫调节回路的新见解。 Specific Aim 3 将开发一种人源化模型，利用 NOD-scid-gamma 菌株增强造血细胞的植入，在人体免疫系统的背景下检查体内自身免疫反应。该模型还将生成独特的人体免疫试剂和工具，最终目标是提供临床前测试平台，以验证研究结果并测试体内免疫调节干预措施。公众健康相关性：自身免疫影响了大约 7% 的美国人口，并且是全世界大多数免疫性肾炎的根源，免疫性肾炎是影响天然和移植器官的慢性肾病的主要原因。该提案检验了抗 GBM 肾炎研究中出现的新范式，抗 GBM 肾炎是一种原型自身免疫性肾炎，其中人类肾脏靶抗原 alpha3(IV)NC1 胶原蛋白已得到很好的表征。因此，抗GBM肾炎是涉及人类肾脏疾病发病机制和免疫调节网络的关键系统。此外，抗 GBM 自身免疫会导致 ANCA 血管炎疾病，可以通过免疫调节 mAb 疗法诱导，并且与抗 II 型胶原自身免疫和类风湿性关节炎具有遗传和免疫学联系。因此，旨在寻找这些疾病的根本原因的拟议研究预计具有广泛的临床意义。新颖的见解和新的工具可以应用于大量患者群体，以推进新的诊断和治疗方法！