Systems Biology Approach to Growth Regulation in Cystic Fibrosis

囊性纤维化生长调节的系统生物学方法

• 批准号: 8091253
• 负责人: Mitchell L Drumm
• 金额: $ 38.47万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-20 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091253
• 关键词: Adipocytes; Adipose tissue; Age; Area; Back; Belief; Biochemical; Biochemical Pathway; Bioinformatics; Biological; Body Size; Body mass index; Cachexia; Cell physiology; Cells; Characteristics; Chronic; Complex; Computer Simulation; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Databases; Diabetes Mellitus; Discipline; Disease; Electrolytes; Endocrine; Endocrine system; Energy Metabolism; Epithelial; Excretory function; Exhibits; Exocrine pancreatic insufficiency; Fingerprint; Functional disorder; Gene-Modified; Genes; Genetic; Genetic Screening; Growth; Health; Height; Homeostasis; Human; Human Genetics; Individual; Infection; Intestines; Link; Liquid substance; Literature; Lung; Lung diseases; Macronutrients Nutrition; Malnutrition; Maps; Measurement; Measures; Messenger RNA; Metabolic; Metabolism; Methods; Modeling; Molecular Biology; Mus; Myeloid Cells; Neurons; Neurosecretory Systems; Obesity; Organ; Outcome; Pathology; Pathway interactions; Patients; Pattern; Physiological; Physiology; Population; Process; Protein Biosynthesis; Pulmonary Function Test/Forced Expiratory Volume 1; Regulation; Resources; Respiratory physiology; Role; Severities; Severity of illness; Signaling Molecule; Smooth Muscle; Sorting - Cell Movement; Surface; Surveys; System; Systems Biology; Technology; Testing; Theoretical model; Tissues; Weight; Work; absorption; base; body system; cystic fibrosis mouse; cystic fibrosis patients; design; falls; genome wide association study; high throughput technology; human disease; indexing; metabolomics; models and simulation; mouse model; nutrition; predictive modeling; pulmonary body; research study; response; uptake

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.

描述（由申请人提供）：患有囊性纤维化（CF）的个体通常死于其疾病的肺部并发症，但CF涉及所有主要器官系统。CF患者的生存率与体重指数密切相关，小鼠模型表明CF中的体型是由于神经内分泌功能、脂肪代谢和肠道功能的复杂相互作用。我们将继续利用小鼠模型来阐明所涉及的途径及其相互作用，在这里，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途径信息，并整理出那些与我们的经验数据一致的。从这些途径，我们将开发计算模型，将预测这些途径的结果时，以特定的方式扰动。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能力。来自这些操作的数据将被输入回生物信息学处理中，并将生成和测试新的或修订的模型，直到生成真正的预测模型。与此同时，正在进行全基因组关联研究，并将检查显示与肺部疾病或体重指数相关的基因，以确定它们是否可以放在小鼠研究产生的通路图上。通过这种迭代过程，我们希望确定新的途径有助于CF病理生理学和/或澄清已知的影响CF严重程度的途径的作用。