Cr2 as a Murine Lupus Susceptibility Gene

主要研究者/项目负责人（最后，第一，中间）：Boackle，Susan A.说明：说明申请的广泛、长期目标和具体目标，并参考项目的健康相关性。简要描述研究设计和实现这些目标的方法。避免总结过去的成就和使用第一人称。本摘要旨在作为一个简洁和准确的描述拟议的工作时，从申请分开。如果申请获得资助，此描述将成为公共信息。因此，不要相信预言/机密信息。不要超过规定的空间。主要的鼠系统性红斑狼疮（SLE）易感基因座Sel对应于独立影响NZM 2410小鼠中对染色质的耐受性丧失的3个基因座。对应于Slelc的同源区间（源自NZW）含有编码补体受体I和2（CR 1/CR2、CD 35/CD 21）的Cr2。CR 1/CR2缺陷与人类和动物模型中的自身免疫性疾病相关。最近已在Slelc CR 1/CR2中鉴定出关键配体结合结构域的结构差异，其导致受体功能的显著损害。这些结果强烈支持的作用，Cr2作为一种疾病的易感基因在Slelc间隔。本提案中概述的项目将致力于表征NZW CR2在NZM 2410狼疮小鼠模型中的作用。具体目的是证明CR2是NZM 2410 Slelc区间的狼疮易感基因，以确定NZW CR2中对耐受性丧失至关重要的结构域，并确定NZW CR2导致耐受性丧失的机制。通过证明在正常基因产物存在下Slelc表型消退，将提供CR2是Slelc基因座中狼疮易感基因的证据。将评估包含含Cr2的窄间隔的重组菌株，以确保CR2功能障碍继续跟踪自身免疫性疾病。将使用用重组蛋白转染的CR2缺陷细胞系以及来自表达各种形式的多态性NZW CR2的BAC转基因小鼠的B细胞来确定导致自身免疫表型的关键受体结构域。最后，改变的NZW CR2等位基因导致B细胞耐受性丧失的机制将使用用于B细胞耐受性的3-83和HEL模型来表征。这些研究将阐明CR2的特定功能，在NZM 2410小鼠模型中受损，可能影响自身免疫性疾病的发展，因此是治疗干预的重要靶点。性能现场=

Principal Investigator/Program Director (Last, first, middle): Boackle, Susan A. DESCRIPTION: State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project. Describe concisely the research design and methods for achieving these goals. Avoid summaries of past accomplishments and the use of the first person. This abstract is meant to serve as a succinct and accurate description of the proposed work when separated from the application. If the application is funded, this description, as is, will become public information. Therefore, do not inctude prophetary/confidentiat information. DO NOT EXCEED THE ,SPACE PROVIDED. The major murine systemic lupus erythematosus (SLE) susceptibility locus, Slel, corresponds to 3 loci independently affecting loss of tolerance to chromatin in the NZM2410 mouse. The congenic interval corresponding to Slelc, derived from NZW, contains Cr2, which encodes complement receptors I and 2 (CR1/CR2, CD35/CD21). CR1/CR2 deficiency has been associated with autoimmune disease in both humans and in animal models. A structural difference in a critical ligand-binding domain has recently been identified in Slelc CR1/CR2 which results in significant impairment in receptor function. These results strongly support the role of Cr2 as a disease susceptibility gene in the Slelc interval. The project outlined in this proposal will be directed towards characterizing the role of NZW CR2 in the NZM2410 mouse model for lupus. The specific aims are to prove that CR2 is the lupus susceptibility gene in the NZM2410 Slelc interval, to identify the structural domains in NZW CR2 that are critical in loss of tolerance, and to determine the mechanisms by which NZW CR2 results in loss of tolerance. Proof that CR2 is the lupus susceptibility gene in the Slelc locus will be provided by demonstrating that the Slelc phenotypes resolve in the presence of normal gene products. Recombinant strains that contain narrowed intervals containing Cr2 will be assessed to ensure that CR2 dysfunction continues to track with autoimmune disease, The critical receptor domains that result in the autoimmune phenotypes will be determined, using both CR2-deficient cell lines transfected with recombinant proteins as well as B cells from BAC transgenic mice that express various forms of the polymorphic NZW CR2. Finally, the mechanisms by which the altered NZW CR2 allele results in loss of B cell tolerance will be characterized using the 3-83 and HEL models for B cell tolerance. These studies will clarify the specific functions of CR2, impaired in the NZM2410 mouse model, that may impact on the development of autoimmune disease and thus be important targets for therapeutic interventions. PERFORMANCE SITE ========================================Section End===========================================