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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（申请人提供）：囊性纤维化（CF）是一种由 CFTR 突变引起的单基因遗传性疾病，呼吸系统疾病是发病和死亡的主要原因。 CF 的中位生存年龄仅为 37 岁，但肺部疾病的严重程度存在很大差异，即使是具有相同 CFTR 基因型（包括 ?F508 纯合子）的患者也是如此。强有力的双胞胎/同胞研究得出结论，遗传因素在疾病严重程度中必定发挥着关键作用。两项针对双胞胎和同胞的转化研究评估了环境与遗传的影响，两者都得出结论，遗传因素在肺部疾病严重程度中发挥着主要甚至大部分作用，遗传力估计范围为 0.54 至 0.89。早期识别 CF 修饰因子的候选基因研究受到样本量小和表型定义不明确的限制。这些限制已由北美 CF 遗传联盟解决，该联盟包括 UNC/CWRU、约翰霍普金斯大学和多伦多的研究小组。基因修饰联盟患者现在正在接受全基因组扫描（Illumina 610K Quad）测试。该 RFA 现在提供了研究基因表达变异在 CF 肺病中的作用以及 SNP/CNV 和表达数据的综合分析的机会。该项目对于定义 CF 肺病的强大分子表型具有巨大的希望，并且我们将处于独特的地位，可以开发 CF 肺病严重程度的分子机制的综合观点。由于大多数 CF 患者现在都是通过新生儿筛查来诊断的，因此每个 CF 患者都可能具有在生命早期确定的分子特征和相关风险。总而言之，同一 CF 患者的表达数据和全基因组 SNP 数据可能会催生 CF（和其他）肺部疾病的各种生物学和临床研究活动，并为 CF 的新型预后和治疗干预措施提供前所未有的机会。与 CF 中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有关，例如哮喘和慢性阻塞性肺病，正如 TGF¿1 中的变异和差异基因表达已经表明的那样。