CHARACTERIZATION OF A NEW MOUSE MODEL FOR LUPUS

狼疮新小鼠模型的表征

• 批准号: 6835641
• 负责人: BING LIM
• 金额: $ 33.37万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-19 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6835641
• 关键词: CHARACTERIZATION; NEW; MOUSE; MODEL; LUPUS

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===========================================

超出所提供的空间。 这项建议的中心目标是利用一种新的突变鼠株来促进对自身免疫性疾病的理解。在基因靶向实验中，我们偶然获得了一种表现出具有狼疮特征的严重淋巴组织增生性和自身免疫性疾病的小鼠品系。这些动物早在3个月大时就发展出一种引人注目的表型，其特征在于以侵袭性方式进展的全身性巨大淋巴结病和脾肿大。此外，动物表现出以严重肾小球肾病和高免疫球蛋白血症为主的自身免疫性病理。最重要的是，动物产生针对双链DNA和Sm抗原的自身抗体，这是系统性红斑狼疮（SLE）的特异性标志物。免疫功能研究显示，这些动物具有在任何其他模型中均未观察到的严重淋巴发育缺陷。通过回交育种，疾病表型从具有靶基因敲除的小鼠中分离，并且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，我们称之为lag（淋巴细胞增生，自身免疫性肾小球肾病）。使用染色体卫星标记，疾病位点被定位到2号染色体的端粒末端。这不是一个以前与自身免疫性疾病有关的区域。通过候选基因方法，发现该疾病是由于RasGRP 1基因的功能丧失突变所致。本研究的主要目的是通过以下几个方面进一步研究RasGRP 1在自身免疫性疾病中的作用：目的1）研究Ras GRPlmut动物的疾病机制;目的2）研究RasGRP突变如何影响T细胞发育;目的3）研究RASGRP 1 MUT等位基因如何影响抗原诱导的T细胞信号传导;目的4）调查人类SLE中RasGRP 1基因突变的证据。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。性能现场=