Integration of Genomics with Genetics - Molecular Phenotypes for CF Lung Disease

基因组学与遗传学的整合 - CF 肺病的分子表型

• 批准号: 7980526
• 负责人: HARA LEVY
• 金额: $ 148.17万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-02-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7980526
• 关键词: Chronic; Clinical; Collaborations; Complex; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Deterioration; Development; Diagnostic; Disease; Disease Progression; Enrollment; Ensure; Epigenetic Process; Exocrine pancreatic insufficiency; Functional disorder; Gene Expression; Genes; Genetic; Genetic Variation; Genomics; Genotype; Immune response; Infection; Inflammatory; Inherited; Lung; Lung diseases; Modification; Molecular Target; Napping; Neonatal Screening; Outcome; Patients; Population Genetics; Pseudomonas aeruginosa; Pulmonary Cystic Fibrosis; Respiratory physiology; Severities; Technology; Variant; Wisconsin; abstracting; clinical phenotype; cystic fibrosis patients; follow-up; genome-wide; molecular phenotype; novel; prognostic; programs; tool

DESCRIPTION (Provided by the applicant) Abstract: Genomic technologies including expression microarrays and genotyping platforms offer unprecedented opportunities to advance our understanding of the contribution of environmental, genetic, and epigenetic factors towards modification of disease progression. Towards this end, we propose to use an integrative genomics approach to identify differentially expressed genes and their biologically relevant genetic variation impacting clinical severity in cystic fibrosis (CF), an inherited multisystem disease characterized by progressive deterioration in lung function and pancreatic insufficiency attributed to dysfunction of a single gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). In 2001, Jansen and Nap proposed combining genome-wide expression data with population genetics to identify sequence variants that regulate gene expression and in turn impact clinical phenotypes. Our premise is that such an approach is relevant to understanding the pathogenic mechanisms responsible for CF and chronic inflammatory lung diseases in general. Our unique multicenter collaboration, incorporating CF patients enrolled in the Wisconsin Newborn Screening Program, will ensure needed longitudinal follow-up of young patients necessary to confirm current findings and define complex associations. The resulting data will define a molecular phenotype of genes involved in early infections of the CF lung by P. aeruginosa and the contribution of host response to clinical outcome. This project has several important implications for identification of functional genetic variation in novel molecular targets and development of novel clinical diagnostic and prognostic tools. Public Health Relevance: Cystic fibrosis (CF) lung disease is characterized by chronic infection by Pseudomonas aeruginosa and is the major cause of morbidity and mortality in CF patients. The resulting data will define a molecular phenotype of genes involved in early infections of the CF lung by P. aeruginosa and the contribution of host response to clinical outcome. This project has several important implications for identification of functional genetic variation in novel molecular targets and development of novel clinical diagnostic and prognostic tools.

描述（申请人提供） 摘要：包括表达微阵列和基因分型平台在内的基因组技术提供了前所未有的机会，以促进我们对环境，遗传和表观遗传因素对改变疾病进展的贡献的理解。 Towards this end, we propose to use an integrative genomics approach to identify differentially expressed genes and their biologically relevant genetic variation impacting clinical severity in cystic fibrosis (CF), an inherited multisystem disease characterized by progressive deterioration in lung function and pancreatic insufficiency attributed to dysfunction of a single gene encoding the cystic fibrosis transmembrane conductance regulator （CFTR）。在2001年，Jansen和NAP提出了将全基因组表达数据与种群遗传学结合起来的，以识别调节基因表达并影响临床表型的序列变体。我们的前提是，这种方法与理解负责CF和慢性炎症性肺部疾病的致病机制有关。我们独特的多中心合作，结合了参加威斯康星州新生儿筛查计划的CF患者，将确保需要对确认当前发现并定义复杂关联的年轻患者进行纵向随访。所得数据将定义铜绿假单胞菌早期感染的基因的分子表型，以及宿主反应对临床结果的贡献。该项目对于鉴定新的分子靶标的功能遗传变异以及新型临床诊断和预后工具的发展具有一些重要的含义。 公共卫生相关性：囊性纤维化（CF）肺部疾病的特征是铜绿假单胞菌慢性感染，是CF患者发病率和死亡率的主要原因。所得数据将定义铜绿假单胞菌早期感染的基因的分子表型，以及宿主反应对临床结果的贡献。该项目对于鉴定新的分子靶标的功能遗传变异以及新型临床诊断和预后工具的发展具有一些重要的含义。