IKK Beta In Intestinal Inflammation

IKK Beta 在肠道炎症中的作用

• 批准号: 6620423
• 负责人: LAURENCE J EGAN
• 金额: $ 11.98万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620423
• 关键词: I kappa B beta; animal breeding; colitis; disease /disorder model; gastrointestinal epithelium; genetically modified animals; laboratory mouse; macrophage; molecular pathology; mucosal immunity; neutrophil; nuclear factor kappa beta; recombinase

Inflammatory bowel disease is a major cause of suffering in the developed world. Pro-inflammatory cytokines, chemokines and eicosanoids are present in high concentrations in inflammatory bowel disease. Many of these inflammatory mediators can be positively regulated by nuclear factor kappa B (NF-kappaB) family of transcription factors. However, it is not known if NF-kappaB activation in vivo promotes intestinal inflammation, or plays a role in protective host responses by inhibiting apoptosis in the inflamed intestine. Our central hypothesis is that NF-kappaB activation in cells of the innate immune system regulates intestinal inflammation and host responses to inflammation in vivo. This hypothesis will be tested by studying the key molecule that activates NF-kappaB, inhibitory kappa B kinase beta (IKKbeta). Studies in specific aim 1 will generate and characterize a transgenic mouse line that expresses cre recombinase exclusively in intestinal epithelial cells. Studies in specific aim 2 will determine the role of IKKbeta in the activation of NF-kappa B in cells of the mucosal innate immune system. Two conditional knockout mouse strains will be generated by cre/loxP-mediated recombinant of the IKKbeta locus: a) Mice that express cre recombinase in intestinal epithelial cells will be crossed with mice bearing a loxP-flanked IKKbeta locus to produce intestinal epithelial IKKbeta knockout mice; b) Existing mice that express cre recombinase in macrophages and neutrophils will be crossed with mice bearing a loxP-flanked IKKbeta locus to produce macrophage and neutrophil IKKbeta knockout mice. Studies in specific aim 3 will determine the role of NF-kappa B activation in the pathogenesis of intestinal inflammation by analzing the course of colitis induced by feeding dextran sulfatesodium to mice that lack IKKbeta in intestinal epithelial cells or in macrophages and neutrophils. The mentored clinical Scientist Development Award will provide me with essential resources with which to perform this research. I will acquire the theoretical and experimental skills to launch a productive independent investigate career with the assistance of this award and of my institution, the Mayo Foundation for Medical Education and Research.

炎症性肠病是发达国家遭受痛苦的主要原因。 促炎性细胞因子，趋化因子和类花生酸酯在炎症性肠病中以高浓度存在。 这些炎症介质中的许多可以受到转录因子的核因子kappa b（NF-kappab）家族的积极调节。 但是，尚不清楚体内NF-kappab激活是否会促进肠道炎症，或者通过抑制发炎肠中的凋亡而在保护性宿主反应中起作用。 我们的中心假设是，先天免疫系统细胞中的NF-kappab激活调节肠炎和宿主对体内炎症的反应。 该假设将通过研究激活NF-kappab，抑制性kappa B激酶β（IKKBETA）的关键分子来检验。 特定目标1中的研究将产生并表征转基因小鼠系，该系仅在肠上皮细胞中表达CRE重组酶。 特定目标2中的研究将确定Ikkbeta在NF-kappa B激活粘膜先天免疫系统中的作用。 Two conditional knockout mouse strains will be generated by cre/loxP-mediated recombinant of the IKKbeta locus: a) Mice that express cre recombinase in intestinal epithelial cells will be crossed with mice bearing a loxP-flanked IKKbeta locus to produce intestinal epithelial IKKbeta knockout mice; b）在巨噬细胞和嗜中性粒细胞中表达CRE重组酶的现有小鼠将与带有Loxp flankp的Ikkbeta基因座的小鼠交叉，以产生巨噬细胞和中性粒细胞Ikkbeta敲除小鼠。 在特定目标3中的研究将确定NF-kappa b激活在肠道炎症的发病机理中的作用，通过对缺乏肠道上皮细胞或巨噬细胞和中性粒细胞中缺乏Ikkkbeta的小鼠喂养葡萄糖硫酸盐诱导的结肠炎。 指导的临床科学家发展奖将为我提供进行这项研究的基本资源。 我将在该奖项和我的机构，梅奥医学教育和研究基金会的协助下启动富有成效的独立调查职业，以启动富有成效的独立调查职业。