Influence of ENaC Regulators on CF Lung Severity

ENaC 调节剂对 CF 肺严重程度的影响

• 批准号: 6855230
• 负责人: SAMUEL M MOSKOWITZ
• 金额: $ 22.74万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-10 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6855230
• 关键词: alleles; chloride channels; clinical research; cystic fibrosis; genetic polymorphism; genetic screening; genotype; human subject; lung disorder; nucleic acid sequence; patient oriented research; phenotype; regulatory gene; respiratory airflow disorder; sodium channel; statistics /biometry

DESCRIPTION (provided by applicant): Cystic fibrosis (CF), an important cause of fatal lung disease in children and young adults, results from genetic deficiency of the CF transmembrane regulator (CFTR). A striking aspect of this disorder is the variability of its lung phenotype: some individuals with CFTR alleles ordinarily associated with severe lung disease (e.g., deltaF508 homozygous) may have only minimal lung disease even in later adulthood. Understanding factors that influence this variability may provide important insights into CF lung disease. A key function of CFTR is to regulate the epithelial sodium channel (ENaC), a major determinant of airway surface hydration. In the setting of CFTR deficiency, excessive sodium absorption via ENaC results in dehydration of airway surface liquid and overlying mucus, impairment of ciliary function, and adhesion of mucus plaques that become a nidus for infection by opportunistic pathogens. Recently, additional ENaC regulators have been identified that represent compelling candidates as modifiers of the CF lung phenotype. Variants of these ENaC regulators may ameliorate mucociliary clearance and result in milder lung disease. The specific aims of this project are: (1) to screen for functional variants of ENaC regulatory genes in individuals with CF, and (2) to evaluate the relationship between ENaC regulator variants and CF lung phenotypes. Variations in ENaC regulatory genes will be sought in two groups of deltaF508 homozygous subjects, one with severe CF lung disease and the other with CF but minimal lung disease. ENaC regulatory genes will be re-sequenced for these subjects to identify variants. Statistical genetic methods will then be used to analyze the association of allele, genotype, and haplotype frequencies of these variants with median values of age- and height-adjusted FEV1 (primary outcome) and measures of airway infection susceptibility secondary outcomes). Identifying ENaC regulatory genes as modifiers of the CF lung phenotype would provide important insights into disease pathogenesis and define novel targets for therapeutic intervention.

描述（由申请人提供）：囊性纤维化（CF）是儿童和年轻人致命性肺部疾病的一个重要原因，是由 CF 跨膜调节因子（CFTR）的遗传缺陷引起的。这种疾病的一个显着方面是其肺部表型的变异性：一些通常与严重肺部疾病相关的 CFTR 等位基因个体（例如 deltaF508 纯合子）即使在成年后期也可能只有轻微的肺部疾病。了解影响这种变异性的因素可能会为 CF 肺病提供重要的见解。 CFTR 的一个关键功能是调节上皮钠通道 (ENaC)，这是气道表面水合的主要决定因素。在 CFTR 缺乏的情况下，ENaC 吸收过多的钠会导致气道表面液体和上层粘液脱水、纤毛功能受损以及粘液斑块粘附，从而成为机会性病原体感染的病灶。最近，已经确定了其他 ENaC 调节剂，它们是 CF 肺表型修饰剂的有力候选者。这些 ENaC 调节剂的变体可能会改善粘液纤毛清除并导致较轻的肺部疾病。该项目的具体目标是：(1) 筛选 CF 个体中 ENaC 调节基因的功能变异，以及 (2) 评估 ENaC 调节基因变异与 CF 肺表型之间的关系。将在两组 deltaF508 纯合受试者中寻找 ENaC 调节基因的变异，一组患有严重的 CF 肺病，另一组患有 CF 但轻微的肺病。 ENaC 调控基因将为这些受试者重新测序以识别变异。然后将使用统计遗传学方法来分析这些变异的等位基因、基因型和单倍型频率与年龄和身高调整的 FEV1 中值（主要结果）以及气道感染易感性测量（次要结果）的关联。鉴定 ENaC 调节基因作为 CF 肺表型的修饰因子将为了解疾病发病机制提供重要见解，并确定治疗干预的新靶点。