Analysis of the inflammatory bowel disease susceptome and resistome using a forward genetics approach

使用正向遗传学方法分析炎症性肠病易感组和耐药组

• 批准号: 112578275
• 负责人: Dr. Katharina Brandl
• 金额: --
• 依托单位: UT Southwestern Medical Center
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/112578275?language=en
• 关键词: Analysis; inflammatory; bowel; disease; susceptome

Inflammatory bowel diseases (IBD), including both ulcerative colitis and Crohn’s disease, are extremely variable in severity, and have strong genetic components, but do not behave as simple Mendelian traits. This suggests that environmental differences between individuals including differences in the intestinal microbiome or alternatively, the cumulative effects of genetic differences at numerous loci may determine whether the disease phenotype is present. In mice, several mutations are known to favor IBD or to inhibit intestinal inflammation. But a comprehensive picture of the pathogenesis of IBD cannot be assembled based on the limited information so far available from genetic analyses, nor can human IBD be stringently ascribed to mutations that are known to be influential in mice. Here we propose to take an unbiased, hypothesis-free view of IBD, using germline mutagenesis to analyze the phenomenon in mice. In specific aim 1, we intend to screen for mutations that cause either susceptibility or resistance to IBD on a defined genetic background using the a mouse model of IBD (the Dextran sodium sulfate (DSS) colitis model), positionally clone these mutations, and form hypotheses concerning the participation of each validated gene in the disease pathogenesis. The mutations that we create will identify candidate loci that may cause IBD disease in humans, point to potential targets for therapy and yield testable hypotheses concerning the involvement of other genes in IBD resistance or susceptibility. Furthermore, in specific aim 2, we will investigate one mutant mouse with a missense error in Mbtps1, encoding the site-1 protease (S1P), which was found to be susceptible for IBD. This proposal aims toward new discoveries about the pathogenesis of IBD, which may eventually lead to new targets or therapies.

炎症性肠病（IBD），包括溃疡性结肠炎和克罗恩病，其严重程度差异很大，并且具有很强的遗传成分，但并不表现为简单的孟德尔特征。这表明个体之间的环境差异，包括肠道微生物组的差异，或者许多基因座遗传差异的累积效应，可能决定是否存在疾病表型。在小鼠中，已知有几种突变有利于 IBD 或抑制肠道炎症。但是，根据迄今为止从遗传分析中获得的有限信息，无法全面了解 IBD 的发病机制，也不能严格地将人类 IBD 归因于已知对小鼠有影响的突变。在这里，我们建议对 IBD 采取公正、无假设的观点，利用种系突变来分析小鼠的这一现象。在具体目标 1 中，我们打算使用 IBD 小鼠模型（葡聚糖硫酸钠 (DSS) 结肠炎模型）在确定的遗传背景下筛选导致 IBD 易感性或耐药性的突变，定位克隆这些突变，并形成有关每个已验证基因参与疾病发病机制的假设。我们创建的突变将识别可能导致人类 IBD 疾病的候选位点，指出潜在的治疗靶点，并产生有关其他基因参与 IBD 耐药性或易感性的可检验假设。此外，在具体目标 2 中，我们将研究一只 Mbtps1 中存在错义错误的突变小鼠，该突变小鼠编码位点 1 蛋白酶 (S1P)，被发现对 IBD 敏感。该提案旨在促进IBD发病机制的新发现，最终可能带来新的靶点或治疗方法。