Molecular Phenotypes for Cystic Fibrosis Lung Disease

囊性纤维化肺病的分子表型

基本信息

批准号：
8109359
负责人：
Michael R Knowles
金额：
$ 71.48万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-24 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8109359
关键词：
Address Adopted Affect Age American Asthma Biological Candidate Disease Gene Cells Chronic Obstructive Airway Disease Cis-Trans Tests Clinical Research Collection Culture Techniques Cultured Cells Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator DNA Data Diagnosis Disease Dissection Environment Epithelial Cells Family Gene Expression Genes Genetic Genetic Risk Genetic Transcription Genome Genomics Genotype Goals Hereditary Disease Heritability Homozygote Human In Vitro Individual Joints Lead Life Lung Lung diseases Lymphocyte Maps Modeling Molecular Molecular Profiling Morbidity - disease rate Mutation Nasal Epithelium Nature Neonatal Screening Organ Outcome Outcome Study Patients Phenotype Play Population Positioning Attribute Pulmonary Cystic Fibrosis RNA Reporting Research Research Activity Risk Role Sample Size Sampling Severities Severity of illness Structure of respiratory epithelium Testing Therapeutic Intervention Time Tissue-Specific Gene Expression Transcript Twin Multiple Birth Twin Studies Validation Variant base biological research case control cell type cystic fibrosis patients design genetic variant genome wide association study lymphoblastoid cell line molecular phenotype mortality novel prognostic small hairpin RNA trait validation studies

项目摘要

DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is a monogenic genetic disorder caused by mutations in CFTR, and respiratory disease is the major cause of morbidity and mortality. The median age of survival in CF is only 37 years, but there is a broad range of disease severity in the lung, even among patients with identical CFTR genotypes, including ?F508 homozygotes. Robust twin/sib studies conclude that genetic factors must play a critical role in disease severity. Two transformational studies of twins and sibs assessed environmental versus genetic influences, and both concluded that genetic factors play a major, or even majority, role in lung disease severity, and heritability estimates ranged from 0.54 to 0.89. Early candidate gene studies to identify CF modifiers were limited by small sample size and poorly defined phenotypes. These limitations have been addressed by a North American CF Genetic Consortium, which includes study groups at UNC/CWRU, Johns Hopkins, and Toronto. Genetic Modifier Consortium patients are now being tested in a whole-genome scan (Illumina 610K Quad). This RFA now provides the opportunity to study the role of gene expression variation in CF lung disease, and the integrated analysis of SNPs/CNVs and expression data. This project holds great promise for defining a robust molecular phenotype for CF lung disease, and we will be uniquely positioned to develop an integrated view of molecular mechanisms underlying CF lung disease severity. Since most CF patients are now diagnosed by neonatal screening, each CF patient could have a molecular signature, and associated risk, established early in life. Taken together, expression data and whole genome SNP data in the same CF patients are likely to spawn a variety of biological and clinical research activity in CF (and other) lung diseases, and provide unprecedented opportunities for novel prognostic and therapeutic interventions in CF. The identification of molecular mechanisms relevant to lung disease severity in CF is also likely to be relevant to more common lung diseases, such as asthma and COPD, as has already been shown for variants and differential gene expression in TGF¿1.

描述（由适用提供）：囊性纤维化（CF）是由CFTR突变引起的一种单基因遗传疾病，呼吸道疾病是发病率和死亡率的主要原因。 CF的生存年龄中位数仅为37岁，但是肺部的疾病严重程度也很广，即使在具有相同CFTR基因型的患者中，包括？F508纯合子。强大的双胞胎/SIB研究包括，遗传因素必须对双胞胎和SIB的两次转化研究评估了环境和遗传影响，并且都得出结论，遗传因素在肺部疾病严重程度中起主要甚至多数的作用，而遗传力估计在0.54至0.89之间。早期的候选基因研究以鉴定CF修饰符受到较小样本量和定义较差的表型的限制。这些局限性已由北美CF遗传联盟解决，其中包括在UNC/CWRU，Johns Hopkins和Toronto的研究小组。遗传修饰符财团患者现在正在全基因组扫描（Illumina 610k Quad）中进行测试。现在，该RFA提供了研究基因表达变异在CF肺疾病中的作用以及SNP/CNV和表达数据的综合分析的机会。该项目具有为CF肺部疾病定义强大的分子表型的巨大希望，并且我们将在CF肺部疾病严重程度下的分子机制的综合视图中占有独特的位置。由于大多数CF患者现在通过新生儿筛查诊断，因此每个CF患者都可以在生命早期建立的分子签名和相关风险。同一CF患者中的表达数据和整个基因组SNP数据可能会在CF（和其他）肺部疾病中产生各种生物学和临床研究活动，并为CF中的新预后和治疗性干预提供了前所未有的机会。 CF中与肺部疾病严重程度相关的分子机制的鉴定也可能与更常见的肺部疾病（例如哮喘和COPD）有关，如TGF。在变体中所示和差异基因表达所示。