Novel Receptor-Ligand Interactions in Glomerulonephritis

描述（由申请人提供）：抗gbm肾炎是一种典型的自身免疫性肾炎，其肾脏靶抗原具有很好的特征，是发现涉及人类肾脏疾病发病机制的关键系统。肾源性表位位于肾小球基底膜内的α 3 (IV) NC1胶原上。最近令人信服的发现表明，存在一种交叉反应性和以前未被怀疑的额外的自身抗原，参与疾病的发病机制，以及各种抗胶原蛋白疾病之间的免疫联系。这些发现表明了自身免疫性疾病调节的显著复杂性，对其的阐明将为疾病的发病、抑制和停止提供新的见解。本研究的目标是鉴定这种第二抗原和新型受体-配体相互作用的分子基础，并探索它们在人体自身免疫和体内疾病发病机制中的作用。这项工作依赖于前沿但经过验证的技术和跨学科合作。Specific Aim 1将使用最先进的和互补的蛋白质组学方法来鉴定参与和调节对alpha3(IV)NC1胶原的致病反应性的未知第二抗原。Specific Aim 2将使用创新的计算预测模型来确定受体-配体结构，这既可以进一步为Aim 1提供信息，也可以为潜在的环境疾病诱因和重叠的自身免疫调节回路提供新的见解。Specific Aim 3将开发一种人源化模型，利用nod -scid- γ菌株增强造血细胞的植入，在人体免疫系统的背景下检测体内自身免疫反应。该模型还将产生独特的人体免疫试剂和工具，最终目标是为临床前测试提供平台，以验证研究结果并在体内测试免疫调节干预措施。

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.