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: 7918932
• 负责人: Mitchell L Drumm
• 金额: $ 38.86万
• 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/7918932
• 关键词: 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; 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）的个体通常会屈服于其疾病的肺并发症，但CF涉及所有主要器官系统。 CF患者的存活与体重指数密切相关，小鼠模型表明CF中的身体大小是由于神经内分泌功能，脂肪代谢和肠功能的复杂相互作用所致。我们将继续利用鼠标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，该计划将援引生物信息学以从文献和数据库中提取途径信息，并与我们的经验数据一致。从这些途径中，我们将开发计算模型，这些模型将以特定方式扰动时预测这些途径的结果。使用遗传和药理学方法，我们将扰动这些途径，并评估它们预测结果的能力。这些操作的数据将回到生物信息学处理中，并将生成新的或修订的模型，直到生成真正的预测模型为止。同时，正在进行一项全基因组协会研究，并将检查显示与肺部疾病或体重指数关联的基因，以确定是否可以将其放置在小鼠研究产生的途径图上。通过这种迭代过程，我们希望确定有助于CF病理生理学的新途径和/或阐明已知影响CF严重性的途径的作用。