CHARACTERIZATION OF A NEW MOUSE MODEL FOR LUPUS

超出提供的空间。这项提议的中心目标是利用一种新的突变小鼠品系来促进对自身免疫性疾病的理解。在基因打靶实验中，我们偶然获得了一种表现为具有狼疮特征的严重淋巴增生性和自身免疫性疾病的小鼠品系。这些动物在3个月大的时候就发展成一种戏剧性的表型，特征是全身巨大的淋巴结病和脾肿大，并以侵袭性的方式进展。此外，动物表现出以严重的肾小球肾病和高免疫球蛋白血症为主的自身免疫病理。最重要的是，这些动物产生了针对双链DNA和Sm抗原的自身抗体，这是系统性红斑狼疮(SLE)的特异性标志。免疫功能研究显示，这些动物有严重的淋巴发育缺陷，这在任何其他模型中都没有见过。通过回交育种，该病的表型与目标基因敲除的小鼠分离，并可作为常染色体隐性性状遗传，孟德尔频率与隐性基因一致。因此，这种疾病是由于另一种基因的自发突变，我们将其命名为LAG(淋巴增殖，自身免疫性肾小球肾病)。利用染色体卫星标记，疾病部位被定位到2号染色体的端粒末端。这是一个以前没有被认为与自身免疫性疾病有关的区域。通过候选基因方法，这种疾病被发现是由于RASGRP1基因的功能丧失突变所致。本研究的中心目标是进一步研究RASGRP1在自身免疫性疾病中的作用)：研究Ras GRPlmut动物的发病机制；目的2)研究RasGRP突变如何影响T细胞的发育；3)研究RASGRP1MUT等位基因如何影响抗原诱导的T细胞信号转导；以及4)寻找RASGRP1基因突变的证据(S)。该项目将有助于了解自身免疫性疾病的不同遗传和分子基础的长期目标，并增加治疗和控制自身免疫性疾病的新方法的知识。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. The central goal of this proposal is to exploit the use of a new mutant murine strain to advance the understanding of autoimmune disorders. During a gene targeting experiment we serendipitously derived a line of mice that manifest a severe lymphoproliferative and autoimmune disease with Lupus features. The animals develop, as early as 3 month old, a dramatic phenotype characterized by generalized massive lymphadenopathy and splenomegaly that progress in an aggressive manner. In addition, the animals manifest autoimmune pathologies dominated by a severe glomerulonephropathy and hyper- immunoglobulinemia. Most significantly, the animals develop auto antibodies against double-stranded DNA and Sm antigen which are specific markers for systemmic lupus erythrematosus (SLE). Immune function studies revealed that the animals have a profound lymphoid developmental defect that has not been seen in any other model. By back-crossing breeding the disease phenotype segregated from mice with the knockout of the targeted gene and is inheritable as an autosomal recessive trait with a Mendelian frequency consistent with a recessive gene. Therefore the disease is due to the spontaneous mutation of another gene which we have named lag (lymphoproliferation, autoimmune glomerulonephropathy). Using chromosomal satellite markers, the disease locus was mapped to the telomeric end of chromosome 2. This is not a region that has been linked before to autoimmune disease. By candidate gene approach the disease was found to be due to a loss-of-function mutation of the RasGRP1 gene. The central goal of this proposal is study further the role of RasGRP1 in autoimmune disease by Aiml):Studying the mechanisms for disease in Ras GRPlmut animals; Aim 2) Studying how RasGRP mutation affect T cell development; Aim3)Studying how RASGRP1MUT allele affect antigen-induced T cell signaling.and Aim 4) Investigating for evidence of mutation(s) of the RasGRP1 gene in human SLE. This project will contribute to a long term goal of understanding the diverse genetic and molecular basis of autoimmune diseases and add to knowledge for new ways to treat and control autoimmune diseases. PERFORMANCE SITE ========================================Section End===========================================