Novel Receptor-Ligand Interactions in Glomerulonephritis

描述（由申请人提供）：抗GBM肾炎是一种原型自身免疫性肾炎，其肾脏靶抗原已得到充分表征，是发现涉及人类肾脏疾病发病机制的关键系统。致肾表位位于肾小球基底膜内的α 3（IV）NC 1胶原上。令人信服的最近的发现表明，存在一个交叉反应和以前未知的额外的自身抗原参与疾病的发病机制，以及不同的抗胶原蛋白疾病之间的免疫联系。这些发现表明自身免疫性疾病调控的显着复杂性，阐明这将提供疾病发作，抑制和逮捕的新见解。该提案的目标是确定这第二种抗原和新的受体-配体相互作用的分子基础，并探索它们在体内参与人类自身免疫和疾病发病机制。这项工作依赖于尖端但经过验证的技术和跨学科合作。Specific Aim 1将使用最先进的互补蛋白质组学方法来鉴定未知的第二抗原，该抗原与α 3（IV）NC 1胶原蛋白结合并调节致病反应性。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，既进一步告知目标1，又为潜在的环境疾病沉淀物和重叠的自身免疫调节回路提供新的见解。Specific Aim 3将开发人源化模型，以在人体免疫系统的背景下检查体内自身免疫应答，使用NOD-scid-gamma菌株增强造血细胞的植入。该模型还将产生独特的人类免疫试剂和工具，最终目标是为临床前测试提供平台，以验证研究结果并测试体内免疫调节干预措施。

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.