CHARACTERIZATION OF A NEW MOUSE MODEL FOR LUPUS

描述（由申请人提供）：本提案的中心目标是利用一种新的突变小鼠菌株来促进对自身免疫性疾病的理解。一种新的小鼠系已经衍生出来，其中动物发展为严重的全身性淋巴结病，并伴有自身免疫性肾小球肾炎和高免疫球蛋白血症。值得注意的是，动物产生针对双链DNA和Sm抗原的自身抗体，这两者都是系统性红斑狼疮（SLE）的特异性标记物。免疫功能研究显示，在其他小鼠自身免疫性疾病模型中未见严重淋巴功能障碍和发育缺陷的结合。这种疾病以孟德尔频率传递，与常染色体基因的隐性突变一致。因此，这种疾病是由一种基因的自发突变引起的，我们将其命名为lag（淋巴增生性自身免疫性肾小球肾病）。利用染色体卫星标记扫描小鼠基因组，初步数据表明，延迟基因的一个假定位点是染色体2的端粒端。这一区域之前并没有与自身免疫性疾病联系起来。这项提议的目标是利用这种非凡的新小鼠模型来了解自身免疫性疾病。在Specific Aim 1中，我们将通过结合定位克隆和候选基因方法来定位和鉴定滞后基因。在目标2中，我们将表征滞后表型的疾病过程，并确定引起疾病的细胞。在目标3中，我们将详细研究滞后突变对T细胞发育的影响。在Aim 4中，我们将研究滞后突变如何影响T细胞功能。为了支持这些研究，将产生各种TCRxlag转基因动物，以帮助研究淋巴细胞的发育、功能和信号传导。我们预计，我们对这种小鼠模型的仔细研究将为理解自身免疫性疾病的多种遗传和分子基础提供大量的新信息。新基因和新途径的鉴定可能会为开发以特定方式而不是全局方式抑制免疫系统的药物发现新的靶点。新的疾病基因的发现也可能对大量自身免疫性疾病患者的管理、护理和诊断非常有用。

DESCRIPTION (provided by applicant): The central goal of this proposal is to exploit the use of a new mutant murine strain to advance the understanding of autoimmune disorders. A new line of mice has been derived in which animals develop a severe generalized lymphadenopathy together with autoimmune glomerulonephritis and hyperimmunoglobulinemia. Significantly, the animals produce auto antibodies against double-stranded DNA and Sm antigen, both of which are specific markers for Systemic Lupus Erythematosus (SLE). Immune function studies showed a combination of severe lymphoid dysfunction and developmental defect not seen in other murine autoimmune disease models. The disease is passed with a Mendelian frequency consistent with a recessive mutation of an autosomal gene. Therefore, the disease arose from a spontaneous mutation of a gene which we have named lag (lymphoproliferative autoimmune glomerulonephropathy). Using chromosomal satellite markers to scan the murine genome, preliminary data indicate that a putative locus for the lag gene is the telomeric end of chromosome 2. This is not a region that has been linked before to autoimmune disease. The goal of this proposal is to exploit this remarkable new murine model to learn about autoimmune disease. In Specific Aim 1, we will map the location of the gene and identify the lag gene by combining positional cloning with a candidate gene approach. In Aim 2 we will characterize the disease process for the lag phenotype and identify the cells causing the disease. In Aim 3 we will examine in detail the effect of the lag mutation on T cell development. In Aim 4 we will investigate how the lag mutation affects T cell function. To support these studies, various TCRxlag transgenic animals will be generated to help the study of lymphocyte development, function and signaling. We anticipate that our proposal to study this murine model carefully will contribute a significant amount of new information for understanding the diverse genetic and molecular bases of autoimmune diseases. The identification of new genes and new pathways may uncover new targets for the development of drugs to suppress the immune system in a specific way, instead of globally. The discovery of new disease genes may also be very useful in the management, care and diagnosis of the large number of patients with autoimmune diseases.