Cr2 as a Murine Lupus Susceptibility Gene

Cr2 作为小鼠狼疮易感基因

• 批准号: 6768766
• 负责人: SUSAN A. BOACKLE
• 金额: $ 29.23万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6768766
• 关键词: Cr2; Murine; Lupus; Susceptibility; Gene

DESCRIPTION (provided by applicant): The major murine systemic lupus erythematosus (SLE) susceptibility locus, Sle1, corresponds to 3 loci independently affecting loss of tolerance to chromatin in the NZM2410 mouse. The congenic interval corresponding to Sle1c, 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 Sle1c 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 Sle1c 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 Sle1c 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 Sle1c locus will be provided by demonstrating that the Sle1c 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.

描述(由申请人提供)：主要的小鼠系统性红斑狼疮(SLE)易感基因Sle1对应于3个独立影响NZM2410小鼠染色质耐受性的基因座。与Sle1c对应的同源区间含有Cr2，编码补体受体1和2(CR1/CR2，CD35/CD21)。CR1/CR2缺乏症在人类和动物模型中都与自身免疫性疾病有关。最近在Sle1c CR1/CR2中发现了一个关键的配体结合域的结构差异，导致受体功能的显着损害。这些结果有力地支持了Cr2作为一个疾病易感基因在Sle1c区间中的作用。本提案中概述的项目将针对NZW CR2在狼疮NZM2410小鼠模型中的作用进行表征。其具体目的是证明CR2是NZM2410 Sle1c间期的狼疮易感基因，鉴定NZW CR2中与耐受性丧失密切相关的结构域，并确定NZW CR2导致耐受性丧失的机制。通过证明Sle1c表型在正常基因产物的存在下分解，将提供CR2是Sle1c基因座上的狼疮易感基因的证据。将对包含Cr2的重组菌株进行评估，以确保CR2功能障碍继续跟踪自身免疫性疾病，将使用导入重组蛋白的CR2缺陷细胞系以及表达各种形式多态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用B细胞耐受性的3-83和HEL模型来表征。这些研究将阐明在NZM2410小鼠模型中受损的CR2的特定功能，这些功能可能会影响自身免疫性疾病的发展，从而成为治疗干预的重要靶点。