Genetics, Genes, and Pathways in Inflammatory Bowel Disease (IBD)

描述(由申请人提供)：本申请涉及广泛的挑战领域(08)基因组学和特定挑战主题08-DK-106：复杂疾病的基因组学。先天免疫系统是抵御有害细菌和病毒的第一道防线。它通过免疫细胞表面称为受体的蛋白质来感知外来入侵者，然后在内部通过一个复杂的网络或生化反应的“电路”传递这一信号，导致释放细胞因子等蛋白质信使，从而引发炎症。在IBD中，先天免疫系统失控或过度激活，导致获得性免疫缺陷。这会对肠道造成损害。我们的目标是研究调节免疫系统的复杂控制机制，以实现保护免受细菌感染和最大限度减少过度炎症组织损害之间的微妙平衡。通过绘制出内部电路，并确定协调这一复杂电路的重要分子‘开关’或控制器，我们可以预见，我们可以加强治疗IBD的新的、更具针对性的药物的合理设计。在过去两年具有里程碑意义的遗传学研究中，许多基因的DNA变异被发现与克罗恩病和溃疡性结肠炎有关。该项目将发现这些基因发现所涉及的生物过程，并确定与这些蛋白质相互作用和工作的新成分。这将涉及将分子生物学、免疫学和计算预测结合在一起，以补充和加快对IBD的实验研究。 公共卫生相关性：在IBD全基因组关联成功的基础上，我们建议使用整合基因组学，使用最先进的文本挖掘、表达和蛋白质组数据，将与克罗恩病和溃疡性结肠炎相关的基因变异放置在决定疾病易感性的相关生物路径中。然后，我们将通过使用功能RNAi和转录分析研究细胞系和患者活检样本，从实验上确定这些基因和变体影响IBD风险的机制。系统地揭示这些分子机制将为疾病生物学提供新的见解，将揭示构成治疗开发的高度优先目标的基因和途径，更广泛地说，将为许多疾病领域的未来研究工作提供一个框架。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic 08-DK-106: Genomics of complex diseases. The innate immune system is the first-line of defense against harmful bacteria and viruses. It senses foreign invaders through proteins called receptors on the surface of immune cells, which then convey this signal internally through a complex network or 'circuitry' of biochemical reactions resulting in the release of protein messengers such as cytokines, which trigger inflammation. In IBD, the innate immune system becomes uncontrollably or excessively over-activated resulting in defective adaptive immunity. This causes damage to the intestinal tract. Our aim is to investigate the complex control mechanisms that regulate the immune system needed to achieve the delicate balance between protecting against bacterial infections and minimizing excessive inflammatory tissue damage. By mapping out the internal circuitry and identifying the important molecular 'switches' or controllers that orchestrate this complicated circuit, we envisage that we can enhance the rational design of new and more specific drugs for IBD. In landmark genetic studies over the past two years, DNA variation in many genes has been found to be associated with Crohn's disease and ulcerative colitis. This project will discover the biological processes that are implicated by these genetic findings and identify new components that interact and work with these proteins. This will involve bringing together molecular biology, immunology and computational predictions to supplement and accelerate experimental investigations into IBD. PUBLIC HEALTH RELEVANCE: Building from the success of genome-wide association in IBD, we propose to use integrative genomics, using state-of-the-art text mining, expression and proteomic data, to place genetic variants associated with Crohn's disease and ulcerative colitis in biological pathways of relevance that determine susceptibility to disease. We will then experimentally identify the mechanisms by which these genes and variants influence IBD risk by studying cell lines and patient biopsy samples using functional RNAi and transcriptional analysis. Systematically revealing these molecular mechanisms will provide novel insights into disease biology, will expose genes and pathways that constitute high priority targets for therapeutic development and, more broadly, will provide a framework for future research efforts across in many disease areas.