Identification and characterisation of the genes and pathways in susceptibility to inflammatory bowel disease

当代遗传学面临的最大挑战之一是理解炎症性肠病、多发性硬化症和精神分裂症等复杂疾病的遗传学。这项应用寻求解开易感基因和环境触发因素之间的复杂相互作用，这些因素共同作用产生炎症性肠病(IBD)。目前对发病率和发病率的估计表明，澳大利亚可能有3万至4万人患有这些慢性疾病，分别称为克罗恩病和溃疡性结肠炎。最近发现了一种克罗恩病的易感基因，概述的项目不仅将把我们的知识扩展到易感基因本身，还将扩展到通过一系列免疫和炎症事件与它们相互作用而产生疾病的基因。这项工作是确定所有IBD易感基因的大型国际努力的一部分，并建立在澳大利亚IBD家庭登记册资源的基础上--澳大利亚范围内的家庭登记册，其中多名成员受到CD或UC的影响。传统的基因作图方法与疾病和正常肠道组织以及患者和对照组细胞系中不同基因表达谱的多项分析相结合。验证性研究包括确定参与典型IBD病理免疫反应的特定组织和细胞类型，以及可能与表达谱相关的特定患者基因和/或表型的特征。所获得的结果将用于确定IBD易感性的基因、导致疾病的突变以及最终用于疾病调控和治疗的治疗目标。

One of the greatest challenges facing contemporary genetics is to understand the genetics of complex diseases such as inflammatory bowel disease, mutiple sclerosis and schizophrenia. This application seeks to unravel the complex interactions between susceptibility genes and environmental triggers that work together to produce the inflammatory bowel diseases (IBD). Current estimates of the prevalence and incidence suggests that there may be 30-40,000 Australians who suffer from these chronic debiltating set of diseases known separately as Crohn's disease and ulcerative colitis. One susceptibility gene for Crohn's disease has been recently been identified and the project outlined will extend our knowledge not only to the susceptibility genes themselves, but also to the genes that interact with them to produce the disease via a cascade of immune and inflammatory events. This work is part of a large international effort to identify all IBD susceptibility genes and builds on the resources of the Australian IBD Familiy Register- an Australia wide register of families in which multiple members are affected by CD or UC. A traditional gene mapping approach is used in concert with mutiple analyses of different gene expression profiles in disease versus normal bowel tissues as well as in cell lines from patients versus controls. Validation studies include identification of the particular tissues and cell types that are involved in the pathological immune response typical of IBD as well as characterisation of specific patient genotypes and- or phenotypes that may correlate with expression profiles. Results obtained will be used to identify genes underlying IBD susceptibility, the mutations that drive the disease and eventually therapeutic targets for modulation and treatment of disease.