Immunobiology of IFRD1, a gene modifying CF lung disease

IFRD1（一种改变 CF 肺病的基因）的免疫生物学

• 批准号: 7741410
• 负责人: Christopher L Karp
• 金额: $ 39.16万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7741410
• 关键词: Biological; Blood Cells; Body Weight decreased; Bone Marrow; Cells; Chronic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Databases; Disease; Environmental Exposure; European; Exhibits; Gene-Modified; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genotype; Goals; Hematopoietic; Heritability; Histone Deacetylase; Histone deacetylase inhibition; Human; Immunobiology; Incidence; Infection; Inflammation; Inflammatory Response; Knowledge; Lung; Lung diseases; Measures; Mediating; Molecular; Morbidity - disease rate; Mus; North Carolina; Pancreatic Diseases; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Production; Pseudomonas aeruginosa; Publishing; Pulmonary Cystic Fibrosis; Regulation; Research; Rodent; Role; Severities; Severity of illness; Techniques; Twin Multiple Birth; United States; Up-Regulation; Variant; Work; airway inflammation; cell type; cohort; cystic fibrosis airway; cystic fibrosis patients; cytokine; genome wide association study; insight; macrophage; mortality; neutrophil; novel therapeutic intervention; p65; programs; public health relevance

DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is the most common, lethal autosomal recessive disorder in the U.S. Novel therapeutic approaches to CF lung disease, the major cause of morbidity and mortality, are clearly needed. Published studies indicate significant heritability of lung disease severity in CF, independent of CFTR genotype. To search for genes modifying CF lung disease, we performed a genome-wide association scan in one cohort of CF patients, with replication of top candidates in an independent cohort. Using this approach, genetic variation in IFRD1 was identified and replicated as a modifier of lung disease severity in CF. IFRD1 is a transcriptional co-regulator that acts in a histone deacetylase (HDAC)-dependent manner. While expressed in numerous cell types, IFRD1 appears to be expressed most highly in neutrophils (PMNs). Our data indicate that PMN differentiation is associated with upregulation of IFRD1 expression; and that PMNs (but not macrophages) from Ifrd1-/- mice have impaired effector function. The inflammatory response in the CF airway is persistently neutrophilic; in turn, the products of activated PMNs appear to be responsible for airway destruction in CF. Our data demonstrate that, after airway infection with P. aeruginosa, Ifrd1-/- mice exhibit significantly slower bacterial clearance; but also significantly less neutrophilic inflammation and disease. This phenotype is strictly dependent upon hematopoietic cell expression of IFRD1. Further, HDAC inhibition leads to specific blunting of airway inflammatory responses in wild type, not Ifrd1-/- mice, indicating that IFRD1 acts in an HDAC-dependent fashion to regulate airway inflammation. Bone marrow transfer techniques and intracellular analysis of cytokine production localized these effects to PMNs. Finally, analysis of PMNs from normal human donors has revealed significant association of IFRD1 polymorphisms with quantitative measures of PMN effector function. Together, these data suggest the inter-related hypotheses that underlie this proposal: (a) IFRD1 is a modifier gene for CF lung disease; (b) IFRD1 modulates the pathogenesis of airway disease in CF through regulation of PMN effector function; and (c) polymorphisms in IFRD1 alter PMN function. The studies in this proposal will define the biological consequences and cellular and molecular mechanisms underlying IFRD1- mediated modulation of PMN function, as well as identify the causal variants in IFRD1 that modify the expression of CF lung disease. PUBLIC HEALTH RELEVANCE: Cystic fibrosis is the most common, lethal autosomal recessive disorder in those with European backgrounds-with an incidence in the United States of approximately 30,000. Lung disease is the major cause of morbidity and mortality in cystic fibrosis. Despite considerable progress in the therapy of cystic fibrosis in recent decades, the median survival of patients with this disease remains around 35 years. There is thus a pressing need for new therapeutic approaches to cystic fibrosis lung disease. We have identified (and validated) a gene that modifies the severity of cystic fibrosis lung disease: IFRD1. The studies in this proposal will define the molecular mechanisms by which IFRD1 modifies lung disease severity in cystic fibrosis, with the long-term goal of developing novel therapeutic approaches to this devastating disease.

描述（由申请人提供）：囊性纤维化（CF）是美国最常见的致死性常染色体隐性遗传病。显然需要CF肺病（发病率和死亡率的主要原因）的新治疗方法。已发表的研究表明，CF的肺部疾病严重程度具有显著的遗传性，与CFTR基因型无关。为了寻找改变CF肺病的基因，我们在一个CF患者队列中进行了全基因组关联扫描，并在一个独立队列中复制了最佳候选基因。使用这种方法，IFRD 1的遗传变异被鉴定并复制为CF中肺部疾病严重程度的修饰因子。IFRD 1是以组蛋白脱乙酰酶（HDAC）依赖性方式起作用的转录共调节因子。虽然在许多细胞类型中表达，但IFRD 1似乎在中性粒细胞（PMN）中表达最高。我们的数据表明，中性粒细胞分化与IFRD 1表达的上调，并从IFRD 1-/-小鼠的中性粒细胞（但不是巨噬细胞）有受损的效应功能。CF气道中的炎症反应是持续的嗜中性的;反过来，活化的PMN的产物似乎是CF中气道破坏的原因。我们的数据表明，在呼吸道感染铜绿假单胞菌后，Ifrd 1-/-小鼠表现出明显较慢的细菌清除;但也明显较少的嗜酸性炎症和疾病。这种表型严格依赖于IFRD 1的造血细胞表达。此外，HDAC抑制导致野生型而不是IFRD 1-/-小鼠气道炎症反应的特异性钝化，表明IFRD 1以HDAC依赖性方式调节气道炎症。骨髓移植技术和细胞内分析细胞因子的产生本地化这些影响的中性粒细胞。最后，对正常人供体中性粒细胞的分析揭示了IFRD 1多态性与中性粒细胞效应器功能的定量测量显着相关。总之，这些数据表明了这一提议背后的相互关联的假设：（a）IFRD 1是CF肺病的修饰基因;（B）IFRD 1通过调节PMN效应器功能调节CF气道疾病的发病机制;（c）IFRD 1的多态性改变PMN功能。本提案中的研究将确定IFRD 1介导的PMN功能调节的生物学后果和细胞和分子机制，以及确定IFRD 1中修饰CF肺病表达的致病变体。公共卫生相关性：囊性纤维化是最常见的，致命的常染色体隐性遗传疾病的欧洲背景，在美国的发病率约为30000。肺部疾病是囊性纤维化发病率和死亡率的主要原因。尽管近几十年来囊性纤维化的治疗取得了相当大的进展，但患有这种疾病的患者的中位生存期仍然在35年左右。因此，迫切需要囊性纤维化肺病的新治疗方法。我们已经确定（并验证）了一个改变囊性纤维化肺病严重程度的基因：IFRD 1。该提案中的研究将确定IFRD 1改变囊性纤维化肺部疾病严重程度的分子机制，长期目标是开发这种毁灭性疾病的新治疗方法。