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：
8306976
负责人：
MARY H. FOSTER
金额：
$ 34.15万
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/8306976
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.

描述（由申请人提供）：抗GBM肾炎，肾脏靶抗原的原型自身免疫性肾炎是良好的特征，是发现涉及人类肾脏疾病发病机理的关键系统。肾脏生成表位位于肾小球基底膜内的α3（IV）NC1胶原蛋白上。令人信服的最新发现表明，参与疾病发病机理的交叉反应性和以前没有引起的额外自我抗原以及多种抗癌疾病之间的免疫联系。这些发现表明自身免疫性疾病调节中的复杂性显着，其阐明将为疾病发作，抑制和逮捕提供新的见解。该提案的目标是确定第二种抗原和新型受体配体相互作用的分子基础，并探索它们在体内对人类自身免疫和疾病发病机理的参与。这项工作依赖于最前沿，但经过验证的技术和跨学科的合作。具体目标1将使用最先进的和互补的蛋白质组学方法来识别参与和调节对α3（IV）NC1胶原蛋白的致病反应性的未知第二抗原。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，以进一步了解目标1，并提供对潜在的环境疾病沉淀物和重叠自身免疫调节电路的新见解。特定的目标3将开发一种人性化模型，以使用点数 - cid-gamma菌株在人类免疫系统的背景下在体内检查自身免疫反应，从而增强造血细胞的植入。该模型还将生成独特的人类免疫试剂和工具，其最终目标是提供临床前测试的平台，以验证研究结果并在体内测试免疫调节干预措施。