Systems Biology Approach to Growth Regulation in Cystic Fibrosis

描述(申请人提供)：囊性纤维化患者通常会死于肺部并发症，但囊性纤维化涉及所有主要器官系统。CF患者的生存与体重指数密切相关，小鼠模型表明，CF患者的身体大小是神经内分泌功能、脂肪代谢和肠道功能复杂相互作用的结果。我们将继续利用小鼠模型来阐明所涉及的路径及其相互作用，这里我们提出了一个计划，将调用生物信息学从文献和数据库中提取路径信息，并筛选出与我们的经验数据一致的路径信息。从这些途径中，我们将开发计算模型，当这些途径受到特定方式的干扰时，将预测这些途径的结果。使用遗传学和药理学方法，我们将扰乱这些途径，并评估它们预测结果的准确性。这些操作的数据将被输入生物信息学处理，并将生成新的或修订的模型并进行测试，直到生成真正的预测模型。与此同时，一项全基因组关联研究正在进行中，显示与肺部疾病或体重指数相关的基因将被检查，以确定它们是否可以放在老鼠研究产生的路径图上。通过这一迭代过程，我们希望找出有助于CF病理生理学的新途径和/或阐明影响CF严重程度的途径的作用。

DESCRIPTION (provided by applicant): Individuals afflicted with cystic fibrosis (CF) typically succumb to pulmonary complications of their disease, but CF involves all of the major organ systems. Survival of CF patients correlates strongly with body mass index, and mouse models indicate that body size in CF is due to a complex interaction of neuroendocrine function, adipose metabolism and intestinal function. We will continue to utilize mouse models to elucidate the pathways involved and their interactions, and here we propose a plan that will invoke bioinformatics to extract pathway information from literature and databases and sort out those that are concordant with our empiric data. From those pathways, we will develop computational models that will predict outcomes of these pathways when perturbed in specific ways. Using genetic and pharmacologic methods, we will perturb those pathways and assess how well they predict outcomes. Data from these manipulations will be entered back into the bioinformatics processing and new or revised models will be generated and tested until truly predictive models are generated. Concurrently, a whole-genome association study is being carried out and genes showing association with pulmonary disease or body mass index will be examined to determine if they can be placed on the pathway maps generated by the mouse studies. By this iterative process, we hope to identify new pathways contributing to CF pathophysiology and/or clarify the role of pathways known to influence CF severity.