Role of SF Gene Cluster in Autoimmunity

超出提供的空间。SLEL同源基因间隔包含一组启动NZM2410小鼠致死性狼疮的自身免疫级联反应的基因。定位克隆分析发现，小鼠1号染色体上含有CD150家族基因(CD48、Lyl08、CSL、CD84、CD244、CD150、CD229)的7个基因簇是导致对核抗原耐受性下降的原因。这些基因调节许多淋巴细胞系的激活阈值和效应器功能。我们对B6和B6Slelb的比较揭示了该基因家族中存在几个结构和调控多态。我们认为这些多态对免疫功能的影响如下：1)评估CD150/CD2家族基因在体内的表达。该基因簇的表达谱将在从B6和B6分离的不同淋巴细胞群中确定。这将通过结合流式细胞术、RT-PCR分析和在单个CD150成员基因的调控元件的控制下产生具有报告结构的转基因小鼠来完成。2)研究CD150家族基因多态性对淋巴细胞功能的影响。将对从B6和B6小鼠分离的B和T细胞进行功能研究。这将使我们能够在其他遗传相同的背景下确定CD150基因簇的多态对淋巴细胞功能的影响。3)建立评估CD150家族成员功能的动物模型。这个目标的目的是创造一种小鼠品系，其中整个CD150基因簇已经使用Cre重组酶和侧翼loxP位点删除。这些小鼠将是研究该基因家族在体内淋巴细胞功能中的作用的关键。此外，这些小鼠将被用来通过BAC转基因拯救来重建CD150家族成员的表达，以评估CD150家族成员单独或组合在免疫功能中的作用。4)探讨CD150簇基因多态性对自身免疫的影响。我们已经开发了跨越CD150基因簇的B6来源(自身免疫抵抗)和129Sv来源(自身免疫倾向)的BAC重叠群，用于产生BAC转基因小鼠。这些基因将与CD150簇缺失小鼠品系结合使用，以确定这些基因单独或组合的自身免疫潜力。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. The Slel congenic interval contains a cluster of genes that initiate the autoimmune cascade leading to fatal lupus in the NZM2410 mouse. Positional cloning analysis has identified a seven gene cluster on mouse chromosome 1 containing the CD150 family of genes (CD48, Lyl08, Csl, CD84, CD244, CD150, CD229) as causative for a breach in tolerance to nuclear antigens. These genes modulate activation thresholds and effector function in many lymphocyte lineages. Our comparison of B6 and B6.Slelb revealed the existence of several structural and regulatory polymorphisms in this gene family. We propose to characterize the impact of these polymorphisms on immune function as follows: 1) To assess the expression of the CD150/CD2 family of genes in vivo. Expression profiles of this gene cluster will be determined in various lymphoctye populations isolated from B6 and B6.Slelb mice prior to and following disease onset. This will be accomplished by a combination of flow cytometry, RT-PCR analysis and the generation of transgenic mice with reporter constructs under the control of regulatory elements of individual CD150 member genes. 2) To characterize the impact of CD150 family gene polymorphisms on lymphocyte function. Functional studies will be performed on B and T cells isolated from B6 and B6.Slelb mice. This will allow us to determine the impact of polymorphisms at the CD150 gene cluster on lymphocyte function in an otherwise genetically identical background. 3) To create an animal model to assess CD150 family member function. The goal of this aim is to generate a mouse strain in which the entire CD150 gene cluster has been deleted using Cre recombinase and flanking LoxP sites. These mice will be essential to study the role of this gene family in lymphocyte function in vivo. In addition, these mice will be used to reconstitute CD150 family member expression by BAC transgenic rescue to assess the role of individual or combinations of CD150 family members in immune function. 4) To assess the impact of the CD150 cluster polymorphisms on autoimmunity. We have developed B6-derived (autoimmune resistant) and 129Sv-derived (autoimmune prone) BAC contigs spanning the CD150 gene cluster for the generation of BAC transgenic mice. These will be used in combination with the CD150 cluster deletion mouse strain to definitively characterize the autoimmune potential of these genes singly or in combination. PERFORMANCE SITE ========================================Section End===========================================