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Regulation of host defense and development by innate-immunity signal transduction system

先天免疫信号转导系统调节宿主防御和发育

基本信息

批准号：
15380201
负责人：
MORIMATSU Masami
金额：
$ 6.78万
依托单位：
Hokkaido University (2004-2005)Iwate University (2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15380201/
关键词：
Innate immunity NF-kappaB LPS Inflammation Embryonic lethality Dermatitis Allergy DNA損傷遺伝子多型 IkappaB

项目摘要

In innate immune system, specific pattern molecules such as LPS bind to Toll-like receptors and activate signal transduction pathway involving NF-kappaB. Recently we identified a novel nuclear IkB molecule, MAIL. In this study we focused on MAIL and other NF-kappaB related molecules.1. Analysis of MAIL deficient miceEmbryonic lethality was observed for about 90% of MAIL deficient mice. Hypoplasia of the liver was suggested to be a possible cause for this embryonic lethality. Remaining 10% of MAIL deficient mice were born alive. These mice developed severe atopic dermatitis-like disease.2. Analysis of transcriptional regulation of the MAIL geneWe cloned LPS-reactive upstream region of the mouse MAIL gene, and analyzed its promoter function by using a series of mutated sequences. An NF-kappaB binding site located at -229 to -220 bp was revealed to be an essential target of MAIL expression. Overexpression of MAIL protein suppressed the LPS-induced promoter activity of the MAIL gene. These data indicate that MAIL expression is upregulated by NF-kappaB, and it is controlled, at least in part, by an autoregulation mechanism.3. Analysis of an NF-kappaB target gene product, BRCA2BRCA2, an NF-kappaB target molecule, plays essential roles for cell growth and embryogenesis through its DNA repair and recombination function. We demonstrated that BRCA2 proteins from the mouse and dog interact with Rad51 recombinase. We found a novel insertion/deletion polymorphism in canine BRCA2, which is located in a nuclear localization signal. This polymorphism was associated with nuclear localization efficiency and mammary tumor morbidity.

在天然免疫系统中，特定模式分子如LPS与Toll样受体结合并激活涉及NF-κ B的信号转导通路。最近，我们发现了一个新的核IkB分子，MAIL。在本研究中，我们重点关注MAIL和其他NF-κ B相关分子. MAIL缺陷小鼠的分析在MAIL缺陷小鼠中观察到约90%的胚胎死亡。肝脏发育不全被认为是这种胚胎致死的可能原因。其余10%的MAIL缺陷小鼠出生时存活。这些小鼠出现了严重的特应性皮炎样疾病。2. MAIL基因的转录调控分析我们克隆了小鼠MAIL基因的LPS反应性上游区，并利用一系列突变序列分析了其启动子功能。发现位于-229至-220 bp的NF-κ B结合位点是MAIL表达的重要靶标。MAIL蛋白的过表达抑制了LPS诱导的MAIL基因启动子活性。这些数据表明MAIL表达受到NF-κ B的上调，并且至少部分受到自动调节机制的控制。3.分析NF-κ B靶基因产物，BRCA 2 BRCA 2，NF-κ B靶分子，通过其DNA修复和重组功能对细胞生长和胚胎发生起重要作用。我们证明了来自小鼠和狗的BRCA 2蛋白与Rad 51重组酶相互作用。我们发现了一种新的插入/缺失多态性在犬BRCA 2，这是位于核定位信号。这种多态性与核定位效率和乳腺肿瘤发病率相关。