Cr2 as a Murine Lupus Susceptibility Gene

Cr2 作为小鼠狼疮易感基因

• 批准号: 7163723
• 负责人: SUSAN A. BOACKLE
• 金额: $ 27.81万
• 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 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7163723
• 关键词: Affect; Alleles; Animal Model; Autoantigens; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Cell Line; Chromatin; Complement 3d Receptors; Complement Receptor; Development; Disease susceptibility; Ensure; Functional disorder; Genetic Polymorphism; Hen Egg Lysozyme; Human; Impairment; Ligand Binding Domain; Link; Lupus; Membrane; Modeling; Mus; Peripheral; Phenotype; Predisposition; Protein Overexpression; Proteins; Recombinant Proteins; Recombinants; Role; Susceptibility Gene; Systemic Lupus Erythematosus; Therapeutic Intervention; Transgenic Mice; Transgenic Organisms; congenic; mouse model; receptor; receptor function

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.

但前提是。 小鼠系统性红斑狼疮(SLE)的主要易感基因座SLE1对应于3个基因座 独立影响NZM2410小鼠对染色质的耐受性丧失。同源区间 对应于Slelc，来源于NZW，含有编码补体受体I和2的Cr2 (CR1/CR2，CD35/CD21)。CR1/CR2缺乏与两者的自身免疫性疾病有关 在人类和动物模型中。最近在一个关键的配体结合域中的结构差异是 在SLELC CR1/CR2中发现，导致受体功能严重受损。这些结果 强烈支持Cr2基因在SLELC区间作为疾病易感基因的作用。中概述的项目 这项建议旨在表征NZW CR2在NZM2410小鼠模型中的作用 狼疮。其具体目的是证明CR2是NZM2410 SLE的易感基因 间隔，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。CR2是狼疮易感性的证据 Slelc基因座的基因将通过证明Slelc表型在存在的情况下分解来提供 正常基因产物。包含含有Cr2的狭窄间隔的重组菌株将被 评估以确保CR2功能障碍继续跟踪自身免疫性疾病，关键受体 将使用两个CR2缺乏的细胞系来确定导致自身免疫表型的结构域 用重组蛋白和表达不同基因的BAC转基因小鼠的B细胞 NZW CR2的多态形式。最后，改变的NZW CR2等位基因导致 B细胞耐受性的丧失将使用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，这可能会影响 自身免疫性疾病的发展，因此成为治疗干预的重要目标。