MAPPING SUSCEPTIBILITY GENES IN MURINE COLITIS

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的复杂相互作用。白介素10(IL10)基因在小鼠体内的基因突变易导致IBD的自发发展。然而，IBD综合征的严重程度和程度由尚不确定的遗传背景修饰物控制。4周龄的C3H小鼠由于IL-10缺乏可在盲肠、近端、中端和远端引起严重的幼年性结肠炎，而B6-IL10-/-在12周龄时几乎没有病变。该计划项目拨款的项目4建议使用数量性状基因座(QTL)定位技术来确定这些不同菌株易感性的遗传基础，并使用这些信息来指示相关的表型，从而指示候选基因，用于在易感IBD的人类中进行测试。这种方法的有效性在先前的支持中得到了验证，在该支持中发现了6个染色体区域，这些区域包含控制葡聚糖硫酸钠诱导的实验性结肠炎的差异菌株易感性的基因。该项目的具体目标是(1)使用遗传分离分析来建立C3H/HeJBir.IL10-/-小鼠中显著更严重结肠炎的结肠炎易感基因座的染色体位置，以及(2)通过产生携带B6假定的抗性等位基因的C3H小鼠的间隔特异性同源基因群以及携带C3H的假定易感等位基因的B6库来验证结肠炎基因座的表型效应。这种方法应该允许对IBD易感背景基因进行精细定位和候选基因测试，这些背景基因需要与不充分抑制的效应群体进行有害的相互作用。在这些小鼠模型中描述易患IBD的遗传机制将为人类的治疗干预提供可能的途径，甚至可能有助于识别同源人类基因。

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.