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Identification of the genes for human diseases by the nucleotide analyses in wide range and developing the model mouse for them

通过广泛的核苷酸分析鉴定人类疾病的基因并为其开发模型小鼠

基本信息

批准号：
11470125
负责人：
KIMURA Minoru
金额：
$ 5.44万
依托单位：
Tokai University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

Based on our previous achievement that HLA region (spanning 1.8 Mb) positioned at the short arm of 6p21. 3 in the human chromosome 6 has already been sequenced with high accuracy, we attempted to identify candidate genes responsible for two human diseases (Bechet's disease [BA] and Psoriasis-[PA]) and create animal models for these two diseases. The following is the achievement we have performed in the past three years.1. A region responsible for PA was confined to a region spanning 89 to 143 kb from the telomere side of HLA-C locus by genetic analyses. In this region, there were one known and 4 novel genes expressed in a skin. Sequencing of this region revealed that one of the 4 novel gene exhibited a significant polymorphism. This gene was termed "SEEK1" and found to overexpress in the skin suffered with PA.2. For the candidate gene for BD, HLA-B gene itself or its neiboring MICA or MICB gene has been considered for the best candidate. However, recent genetic analysis revealed that HLA-B51 gene is the responsible gene for BD.3. We produced several transgenic (Tg) lines carrying a 30-kb fragment containing SEEK1 gene. Further analysis of these lines is now underway.4. We have already produced Tg lines carrying MICA or MICB gene, just prior to decision that HLA-B51 gene is the responsible gene for BD. These MICA or MICB Tg lines exhibited several abnormalities such as reduction in the nubmer of leukocytes and body weight, and hyperkeratosis in the skin, suggesting possible involvement of these genes in the pathogenesis of BD.5. We also produced Tg lines carrying HLA-B51 and human b2-microglobulin genes and found that in these mice expression of HLA-B51 molecules on the cell surface was greatly elevated. Mice carrying human b2-microglobulin (b2m) and HLA-B51 genes, but lacking mouse b2m gene are now successfully produced using b2m-knock out mice.

根据我们以前的研究结果，HLA区域（跨度为1.8Mb）位于6p 21的短臂。由于人类第6号染色体上的第3个基因已经被高精度地测序，我们试图鉴定两种人类疾病（Bechet病[BA]和Psb-[PA]）的候选基因，并建立这两种疾病的动物模型。以下是我们在过去三年中取得的成就。通过遗传分析，PA的一个区域被限制在HLA-C基因座的端粒侧的一个跨度为89至143 kb的区域。在该区域，有一个已知的和4个新的基因在皮肤中表达。测序结果表明，其中一个新基因具有明显的多态性。该基因被称为“SEEK 1”，并发现在患有PA的皮肤中过度表达。对于BD的候选基因，HLA-B基因本身或其邻近的云母或MICB基因被认为是最佳候选基因。然而，最近的遗传学分析表明，HLA-B51基因是BD的责任基因。我们产生了几个转基因（Tg）线携带30 kb的片段含有SEEK 1基因。目前正在对这些线路进行进一步分析。我们已经产生了携带云母或MICB基因的Tg系，就在决定HLA-B51基因是BD的责任基因之前。这些云母或MICB Tg系表现出几种异常，如白细胞和体重的nubmer减少，皮肤角化过度，表明这些基因可能参与BD的发病机制。我们还产生了携带HLA-B51和人β 2-微球蛋白基因的Tg系，并发现在这些小鼠中，细胞表面上HLA-B51分子的表达大大升高。目前，利用b2 m基因敲除小鼠成功地产生了携带人b2-微球蛋白（b2 m）和HLA-B51基因但缺乏小鼠b2 m基因的小鼠。