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CHARACTERIZATION OF A NEW MOUSE MODEL FOR LUPUS

狼疮新小鼠模型的表征

基本信息

批准号：
7163025
负责人：
BING LIM
金额：
$ 31.64万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/7163025
关键词：
Affect Animals Antibodies Apoptosis Autoimmune Diseases Autoimmune Process Back Bone Marrow Cells Breeding CD4 Positive T Lymphocytes Candidate Disease Gene Caring Cell physiology Cells Chromosomes, Human, Pair 2 Cloning Data Defect Development Diagnosis Disease Disease model Employee Strikes Enlargement of lymph nodes Frequencies Gene Mutation Gene Targeting Gene Transfer Genes Genome Glomerulonephritis Goals Grant Hematopoietic Immune Immune system Immunology Knock-out Knowledge Learning Link Location Lupus Lymphatic Diseases Lymphocyte Lymphoid Malignant Neoplasms Maps Mediating Modeling Molecular Molecular Genetics Mus Mutation NCI Center for Cancer Research Names Nature Numbers Patients Phenotype Population Process Research Personnel Retroviridae Scanning Sm antigen T-Cell Development T-Lymphocyte Testing Transgenic Animals Transgenic Organisms Wild Type Mouse base disease phenotype drug development ds-DNA genetic linkage analysis immune function mouse genome mouse model mutant positional cloning research study response

项目摘要

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 hyper- immunoglobulinemia.. Significantly, the animals produce auto antibodies against double-stranded DNA and Sm antigen both of which are specific markers for Systemmic Lupus Erythrematosus (SLE). Immune function studies showed a combination of severe lymphoid dysfuntion and developmental defect not seen in other murine autoimmune disease model. 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 indicates 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, we will map the location of the gene and identify the lag gene by combining postional cloning with candidate gene approach. In Aim 2 we willl characterize the disease process for the lag phenotype and identify the cells causing the disease. In Aim3 we will examine in detail the effect of the lag mutaiton on T cell development. In Aim 4 we will investigate how the lag mutation affect 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 to understanding the diverse genetic and molecular basis of autoimmune diseases. The identification of new genes and new pathwyas 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..

该提案的中心目标是利用新的突变鼠株来推进了解自身免疫性疾病一种新的小鼠品系已经被培育出来，严重的全身性淋巴结病以及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的自身抗体， Sm抗原是系统性红斑狼疮（SLE）的特异性标志物。免疫功能研究显示，严重的淋巴功能障碍和发育缺陷的组合，在其它鼠自身免疫性疾病模型中。这种疾病以孟德尔频率传播常染色体基因的隐性突变因此，这种疾病是由自发突变引起的。我们称之为lag（淋巴增生性自身免疫性肾小球肾病）。使用染色体卫星标记扫描小鼠基因组，初步数据表明，一个假定的基因座，因为lag基因是2号染色体的端粒末端。这不是一个以前被链接到自身免疫性疾病这项计划的目的是利用这种新的小鼠模型来学习关于自身免疫性疾病在具体目标中，我们将绘制基因的位置并识别滞后基因将定位克隆与候选基因方法相结合。在目标2中，我们将描述疾病的特征处理滞后表型并鉴定引起疾病的细胞。在Aim3中，我们将详细研究滞后突变对T细胞发育的影响。在目标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转基因动物以帮助治疗。淋巴细胞发育、功能和信号传导的研究。我们预计，我们的研究建议，小鼠模型的仔细将有助于大量的新信息，以了解不同的自身免疫性疾病的遗传和分子基础。新基因和新途径的鉴定可能会为开发以特定方式抑制免疫系统的药物发现新的靶点而不是全球范围内。新的疾病基因的发现也可能在管理、护理和治疗方面非常有用。并诊断出大量的自身免疫性疾病患者。