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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

基本信息

批准号：
8316178
负责人：
KASPER HOEBE
金额：
$ 38.03万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8316178
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

项目摘要

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.

囊性纤维化(CF)是美国最常见的致命性常染色体隐性遗传病。治疗慢性肺病的方法显然是必要的，它是导致发病率和死亡率的主要原因。已出版研究表明，慢性肺病患者肺部疾病严重程度的显著遗传力与CFTR型无关。至我们在一个队列中进行了全基因组关联扫描，寻找与CF肺部疾病相关的基因在一个独立的队列中复制排名靠前的候选患者。使用这种方法，基因 IFRD1的变异被识别和复制，作为CF肺部疾病严重程度的修饰性指标。 IFRD1是一种转录辅助调节因子，以组蛋白脱乙酰酶(HDAC)依赖的方式发挥作用。虽然IFRD1在多种细胞类型中都有表达，但在中性粒细胞(PMN)中的表达似乎最高。我们的数据表明，PMN的分化与IFRD1表达上调有关； Ifrd1-/-小鼠的中性粒细胞(但不是巨噬细胞)的效应器功能受损。炎症反应持续的中性粒细胞；反过来，激活的PMN的产物似乎是负责的用于CF中的呼吸道破坏。我们的数据表明，在呼吸道感染铜绿假单胞菌后，Ifrd1-/- 小鼠表现出明显较慢的细菌清除；但中性粒细胞炎症和疾病。这种表型严格依赖于IFRD1的造血细胞表达。此外，HDAC 抑制导致野生型而不是Ifrd1/-小鼠的呼吸道炎症反应特异性钝化，表明 IFRD1以依赖HDAC的方式发挥作用，调节呼吸道炎症。骨髓移植细胞因子产生的技术和细胞内分析将这些影响定位于中性粒细胞。最后，分析了从正常人的中性粒细胞中发现IFRD1基因的多态性与 PMN效应器功能的定量测量。综上所述，这些数据表明了作为这一提议基础的相互关联的假设：(A)IFRD1是一个慢性阻塞性肺疾病的修饰基因；(B)IFRD1通过以下途径调节慢性阻塞性肺疾病的发病机制中性粒细胞效应器功能的调节；以及(C)IFRD1基因的多态性改变中性粒细胞功能。这方面的研究该提案将定义IFRD1背后的生物学后果和细胞和分子机制- 介导PMN功能的调节，以及识别IFRD1中改变PMN功能的原因变体慢性阻塞性肺疾病的临床表现。