In vivo systems biology of inflammatory response in the intestinal epithelium

描述(申请人提供)：炎症性肠病(IBD)是一种以持续的、无法控制的肠道刺激为特征的衰弱疾病。美国有100多万人患有这种疾病，这种疾病可以持续几十年。IBD是一种复杂的自身免疫性疾病，由免疫系统和肠道上皮之间的沟通障碍引起。关于IBD的炎性成分有丰富的知识，但对该病的上皮方面知之甚少。在此背景下，我们的目标是在分子水平上了解肠上皮对急性和慢性炎症刺激的反应。从大规模的信号研究中越来越清楚的是，人们不能通过孤立地检查单个分子通路来完全理解细胞对给定刺激的反应。此外，体外实验系统未能捕捉到对疾病发生和发展至关重要的生物学复杂性，例如细胞分化状态或细胞与细胞之间的相互作用。正因为如此，我们的目标是开发在体肠道上皮细胞信号对炎性刺激的反应的计算模型。这些模型将为调节肠道上皮如何对炎症刺激做出反应的途径提供新的见解。我们研究的一个中心方面是假设由突变的K-RAS和N-RAS激活的信号通路调节肠上皮对炎症刺激的反应。通过在我们的实验系统中对RAS功能进行基因操作，我们将能够改进我们的计算模型，将这些模型置于炎症反应的整个细胞网络中的辅蛋白上。最后，我们的计算分析将确定潜在的治疗靶点，以调节肠道上皮内的炎症反应。目前用于治疗IBD的所有治疗方法都针对疾病的免疫成分，从长远来看基本上是无效的。我们的目标是通过专注于保护肠道免受炎症的方法，为这种复杂疾病的研究做出独特的贡献。我们预计，同时治疗炎性和上皮成分的IBD将在患者中产生更强劲和持续的临床反应。最终，这些研究将拓宽我们对导致IBD的分子途径的了解，并可能对许多患有这种可怕疾病的患者的健康和福祉产生直接影响。

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is a debilitating disease that is characterized by constant, uncontrolled irritation of the intestine. Over 1 million people in the United States suffer from this disease, which can persist for decades. IBD is a complex autoimmune disease that results from faulty communication between the immune system and the intestinal epithelium. There is a wealth a knowledge pertaining to the inflammatory component of IBD, but little is known about the epithelial aspects of the disease. In this context, our goal is to understand, at the molecular level, how the intestinal epithelium responds to acute and chronic inflammatory stimuli. It is increasingly clear from large-scale studies of signaling that one cannot fully understand how a cell responds to a given stimulus by examining a single molecular pathway in isolation. Moreover, in vitro experimental systems fail to capture the biological complexity, for example cellular differentiation state or cell- cell interaction, that is of central importance to disease onset and progression. Because of this, we aim to develop computational models of cellular signaling in response to inflammatory stimuli in vivo in the intestinal epithelium. These models will provide novel insights into the pathways that regulate how the intestinal epithelium responds to inflammatory stimuli. A central aspect of our study is the hypothesis that signaling pathways activated by mutant K-Ras and N-Ras modulate the response of the intestinal epithelium to inflammatory stimuli. By genetically manipulating Ras function in our experimental system, we will be able to refine our computational models to place these on coproteins within the context of the entire cellular network of inflammatory response. In the end, our computational analysis will identify potential therapeutic targets to modulate the inflammatory response within the intestinal epithelium. All of the treatments currently used to treat IBD target the immune component of the disease and are largely ineffective over the long term. Our goal it to make a unique contribution to the study of this complex disease by focusing on ways to protect the intestine from the inflammation. We expect that combining therapies to treat both the inflammatory and epithelial components of IBD will result in more robust and sustained clinical responses in patients suffering from the disease. In the end, these studies will broaden our knowledge of the molecular pathways that contribute to IBD and may have a direct impact on the health and well being of many patients suffering from this terrible disease.