MAPPING SUSCEPTIBILITY GENES IN MURINE COLITIS

绘制小鼠结肠炎的易感基因图谱

• 批准号: 6190084
• 负责人: EDWARD H LEITER
• 金额: $ 15.42万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6190084
• 关键词: artificial chromosomes; colitis; genetic mapping; genetic susceptibility; histopathology; inflammatory bowel diseases; interleukin 10; laboratory mouse; molecular cloning; nucleic acid sequence; phenotype; polymerase chain reaction; quantitative trait loci

Pathogenesis if inflammatory bowel disease (IBD) in humans is multi- factorial, involving complex interactions among genetic, environmental, and immunological factors. Genetic disruption of the Interleukin-10 ((Il10) gene in mice predisposes to spontaneous development of IBD. However, the severity and extent of the IBD syndrome is controlled by as yet unidentified genetic background modifiers. A severe juvenile-onset colitis in cecum, proximal, middle, and distal colon is elicited by IL-10 deficiency in C3H mice by 4 weeks of age, whereas the B6-IL10-/- have developed little or no lesions by 12 weeks of age. Project 4 of this Program Project grant proposes to use quantitative trait locus (QTL) mapping techniques to identify the genetic basis for these differential strain susceptibilities, and to use this information to indicate relevant phenotypes and thus, candidate genes, for testing in IBD-susceptible humans. The validity of this approach was demonstrated during the previous support in which 6 chromosomal regions were identified that contained genes controlling differential strain susceptibility to experimental colitis induced by dextran sulfate sodium. The specific aims of the project are (1) to use genetic segregation analyses to establish the chromosomal locations of colitis susceptibility loci that confer significantly more severe colitis in C3H/HeJBir.IL10-/- mice and (2) to validate phenotypic effects of colitis loci by producing interval-specific congenic stocks of C3H mice carrying putative resistance alleles from B6, and reciprocally, B6 stocks carrying putative susceptibility alleles from C3H. This approaches should allow fine mapping and candidate gene testing for IBD-predisposing background genes required to interact deleteriously with an inadequately suppressed effector population. Delineation of the genetic mechanisms predisposing to IBD in these mouse models will suggest likely pathways for therapeutic intervention in humans and possibly even allow identification of homologous human genes.

人类炎症性肠病（IBD）的发病机制是多因素的，涉及遗传、环境和免疫因素之间复杂的相互作用。小鼠白细胞介素-10 （Il10）基因的遗传破坏易导致IBD的自发发展。然而，IBD综合征的严重程度和程度是由尚未确定的遗传背景修饰因子控制的。在4周龄的C3H小鼠中，IL-10缺乏可引起盲肠、近端、中端和远端严重的幼年性结肠炎，而b6 - IL-10 -/-在12周龄时几乎没有病变。本项目的项目4建议使用数量性状位点（QTL）定位技术来确定这些差异菌株敏感性的遗传基础，并使用这些信息来指示相关表型，从而确定候选基因，以便在ibd易感人群中进行测试。该方法的有效性在之前的支持中得到了证明，其中鉴定出6个染色体区域包含控制差异菌株对葡聚糖硫酸钠诱导的实验性结肠炎的易感性的基因。该项目的具体目的是：(1)使用遗传分离分析来确定C3H/HeJBir中结肠炎易感位点的染色体位置，这些易感位点赋予更严重的结肠炎。(2)通过产生携带来自B6的推定抗性等位基因的C3H小鼠的间隔特异性基因群，以及B6携带来自C3H的推定易感等位基因的B6小鼠的间隔特异性基因群，来验证结肠炎位点的表型效应。这种方法应该允许对ibd易感背景基因进行精细的定位和候选基因检测，这些基因需要与不充分抑制的效应群体有害地相互作用。在这些小鼠模型中描述易患IBD的遗传机制将为人类治疗干预提供可能的途径，甚至可能允许鉴定同源的人类基因。