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

描述（由申请人提供） 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疾病进展的影响的理解。为此，我们建议使用整合基因组学的方法来确定差异表达的基因及其生物学相关的遗传变异影响囊性纤维化（CF）的临床严重程度，囊性纤维化是一种遗传性多系统疾病，其特征是肺功能和胰腺功能不全的进行性恶化，归因于编码囊性纤维化跨膜传导调节因子（CFTR）的单个基因的功能障碍。2001年，Jansen和Nap提出将全基因组表达数据与群体遗传学相结合，以确定调节基因表达并进而影响临床表型的序列变异。我们的前提是，这样的方法是相关的理解的致病机制，CF和慢性炎症性肺疾病的一般。我们独特的多中心合作，包括CF患者参加了威斯康星州新生儿筛查计划，将确保必要的纵向随访的年轻患者，以确认目前的结果和定义复杂的关联。所得到的数据将定义参与铜绿假单胞菌对CF肺的早期感染的基因的分子表型以及宿主应答对临床结果的贡献。该项目对识别新型分子靶点的功能性遗传变异和开发新型临床诊断和预后工具具有重要意义。 公共卫生相关性：囊性纤维化（CF）肺疾病的特征是铜绿假单胞菌的慢性感染，是CF患者发病率和死亡率的主要原因。所得到的数据将定义参与铜绿假单胞菌对CF肺的早期感染的基因的分子表型以及宿主应答对临床结果的贡献。该项目对识别新型分子靶点的功能性遗传变异和开发新型临床诊断和预后工具具有重要意义。

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.