CHARACTERIZATION OF A NEW MOUSE MODEL FOR LUPUS

狼疮新小鼠模型的表征

• 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
• 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

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品系来推进 了解自身免疫性疾病。一个新的小鼠品系已经诞生，其中动物发育出一种 严重全身性淋巴结肿大并伴有自身免疫性肾小球肾炎和高血压 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，并且 Sm 抗原都是系统性红斑狼疮 (SLE) 的特异性标志物。免疫 功能研究显示，未见严重淋巴功能障碍和发育缺陷的组合 在其他小鼠自身免疫性疾病模型中。该疾病的传播频率与孟德尔频率一致 具有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 我们将其命名为 lag（淋巴增殖性自身免疫性肾小球肾病）基因。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位点 因为滞后基因是 2 号染色体的端粒末端。这不是之前已连接的区域 自身免疫性疾病。该提案的目标是利用这种非凡的新小鼠模型来学习 关于自身免疫性疾病。在Specific Aim中，我们将绘制基因的位置图并识别滞后基因 通过将定位克隆与候选基因方法相结合。在目标 2 中，我们将描述该疾病的特征 滞后表型的过程并识别引起疾病的细胞。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 转基因动物来帮助 研究淋巴细胞的发育、功能和信号传导。我们预计我们的研究提案 仔细研究小鼠模型将为理解不同的物种提供大量新信息 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 可能会发现开发以特定方式抑制免疫系统的药物的新靶点 而不是全球范围内。新疾病基因的发现也可能对管理、护理非常有用 以及大量自身免疫性疾病患者的诊断。

项目成果

The molecular basis of ageing in stem cells.

干细胞衰老的分子基础。

• 发表时间: 2007-01
• 影响因子: 5.3
• 作者: Tam, Wai;Ang, Yen;Lim, Bing
• 通讯作者: Lim, Bing

Effects of ectopic Nanog and Oct4 overexpression on mesenchymal stem cells.

异位 Nanog 和 Oct4 过表达对间充质干细胞的影响。

• 发表时间: 2009-09
• 影响因子: 4
• 作者: Liu, Tong Ming;Wu, Ying Nan;Guo, Xi Min;Hui, James Hoi Po;Lee, Eng Hin;Lim, Bing
• 通讯作者: Lim, Bing

Identification of common pathways mediating differentiation of bone marrow- and adipose tissue-derived human mesenchymal stem cells into three mesenchymal lineages.

鉴定介导骨髓和脂肪组织来源的人间充质干细胞分化成三种间充质谱系的常见途径。

• 发表时间: 2007-03
• 作者: Liu, Tong Ming;Martina, Monique;Hutmacher, Dietmar W;Hui, James Hoi Po;Lee, Eng Hin;Lim, Bing
• 通讯作者: Lim, Bing

A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes.

一种基于模式的方法，用于识别 MicroRNA 结合位点及其相应的异源双链体。

• 发表时间: 2006-09-22
• 影响因子: 64.5
• 作者: Miranda, Kevin C;Huynh, Tien;Tay, Yvonne;Ang, Yen;Tam, Wai;Thomson, Andrew M;Lim, Bing;Rigoutsos, Isidore
• 通讯作者: Rigoutsos, Isidore

Genome-wide mapping of RELA(p65) binding identifies E2F1 as a transcriptional activator recruited by NF-kappaB upon TLR4 activation.

RELA(p65) 结合的全基因组图谱将 E2F1 识别为 TLR4 激活后 NF-kappaB 招募的转录激活因子。

• 发表时间: 2007-08-17
• 影响因子: 16
• 作者: Lim, Ching;Yao, Fei;Wong, Joyce Jing;George, Joshy;Xu, Han;Chiu, Kuo Ping;Sung, Wing;Lipovich, Leonard;Vega, Vinsensius B;Chen, Joanne;Shahab, Atif;Zhao, Xiao Dong;Hibberd, Martin;Wei, Chia;Lim, Bing;Ng, Huck;Ruan, Yiju
• 通讯作者: Ruan, Yiju