Functional Genetics in Idiopathic Pulmonary Fibrosis

特发性肺纤维化的功能遗传学

• 批准号: 8754053
• 负责人: David Albert Schwartz
• 金额: $ 21.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8754053
• 关键词: Accounting; Acids; Adhesions; Air; Alleles; Alveolar; Asbestos; Biological; Bleomycin; Cells; Chronic; Collagen; Data; Defect; Development; Engineering; Epithelial Cells; Etiology; Gene Expression; Genetic; Genetic Engineering; Genotype; Goals; Hamman-Rich syndrome; Host Defense; Human; Hypoxia; In Vitro; Individual; Infection; Infectious Agent; Inflammation; Injury; Interleukin-13; Interleukin-17; Interleukin-6; Interstitial Lung Diseases; Lesion; Life; Liquid substance; Lung; Lung diseases; MUC5B gene; Measures; Mechanical Stress; Modeling; Molecular; Mouse Strains; Mucociliary Clearance; Mucous body substance; Mus; Nose; Odds Ratio; Outcome Measure; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Peripheral; Phase; Proteins; Public Health; Pulmonary Fibrosis; Resistance; Risk; Risk Factors; Rotation; Signal Transduction; Stress; System; Testing; Wounds and Injuries; abstracting; airway epithelium; base; cell injury; cigarette smoking; cytokine; genetic risk factor; genome wide association study; in vivo; injury and repair; lung injury; novel; pathogen; promoter; protein expression; public health relevance; repaired; research study; response; risk variant

DESCRIPTION (provided by applicant): The overall goal of this proposal is to understand how dysregulated MUC5B results in the development of fibroproliferative lung disease. This approach is based on two recent advances. First, we have discovered that MUC5B is the strongest risk factor, genetic and otherwise, for familial and sporadic forms of idiopathic pulmonary fibrosis (IPF). The MUC5B promoter SNP rs35705950 has been validated as a risk variant for IPF in six independent studies (1-6), is the strongest known risk factor for the development of both familial and sporadic forms of IPF (odds ratio H 4-8 per allele), and represents a risk variant observed in at least half of the cases of either familial or sporadic IPF Although our GWAS identified 3 established (TERC, TERT, and MUC5B) and 7 novel pulmonary fibrosis loci (5), the MUC5B promoter SNP remained the strongest genetic signal associated with pulmonary fibrosis (OR=4.51 [95%CI=3.91-5.21]; P = 7.21x10-95), and subsequent analyses indicate that this SNP accounts for ~39% of the risk of developing IPF. Second, our findings suggest that MUC5B appears to be involved in the pathogenesis of IPF. IPF patients have significantly more MUC5B gene expression than unaffected subjects (1), the MUC5B promoter SNP is associated with enhanced MUC5B expression in both unaffected subjects (1) and patients with IPF (7), MUC5B message and protein are expressed in the pathologic lesions of IPF (1, 8), and we have recently found that Muc5b deficient mice are resistant to both bleomycin and asbestos models of fibroproliferation (see preliminary data). Based on these observations, we speculate that the MUC5B promoter SNP places individuals at risk of developing IPF via chronic mucus hypersecretion and accumulation in the peripheral airspace that impairs mucocilliary transport, results in mucus adhesion in the bronchoalveolar region, and consequently induces and potentiates chronic inflammation and injury (1, 10). We have engineered an efficient, tiered approach to understand how dysregulated MUC5B results in the development of fibroproliferative lung disease. While the R21 phase of the proposal will use an in vitro human cell-derived system to explore basic biological responses to MUC5B, the R33 phase of the proposal will test these findings in three established strains of mice (CCSP-Muc5bTg, SPC-Muc5bTg, and Muc5b-/- mice). Based on what is known about IPF and MUC5B, we hypothesize that chronic mucus hypersecretion impairs mucociliary transport and results in persistent cell injury causing impaired host defense and excessive repair and leading to the development of fibroproliferative lung disease.

描述（由申请人提供）：该提案的总体目标是了解失调的MUC5B如何导致纤维增生性肺部疾病的发展。这种方法基于最近的两个进步。首先，我们发现MUC5B是家族性和零星形式的特发性肺纤维化（IPF）的遗传和零星形式的最强危险因素。 The MUC5B promoter SNP rs35705950 has been validated as a risk variant for IPF in six independent studies (1-6), is the strongest known risk factor for the development of both familial and sporadic forms of IPF (odds ratio H 4-8 per allele), and represents a risk variant observed in at least half of the cases of either familial or sporadic IPF Although our GWAS identified 3 established (TERC, TERT和MUC5B）和7个新型肺纤维化基因座（5），MUC5B启动子SNP仍然是与肺纤维化相关的最强遗传信号（OR = 4.51 [95％CI = 3.91-5.21]; P = 7.21x10-95），随后的分析表明，该SNP的风险为39％的估计估计〜39％。其次，我们的发现表明MUC5B似乎参与了IPF的发病机理。 IPF患者的MUC5B基因表达明显高于未受影响的受试者（1），MUC5B启动子SNP与未受影响的受试者（1）和IPF（7）患者的MUC5B表达增强相关，MUC5B消息和蛋白质在IPF（1，8）的病理学疾病中表达，并且在MUC5B（1，8）中表达了MIC的表达，并且我们已经抗MUC5B（1，8）。石棉模型的纤维增殖模型（请参阅初步数据）。基于这些观察结果，我们推测MUC5B启动子SNP使个人面临通过慢性粘液过度分泌发展IPF的风险，并在外围空域中积累损害粘膜循环的人，会导致粘液粘附区域的粘液粘附，从而诱导和增强型和增强型炎症和损伤（1，1，1，10）。 我们已经设计了一种有效的，分层的方法，以了解失调的MUC5B如何导致纤维增生性肺部疾病的发展。 While the R21 phase of the proposal will use an in vitro human cell-derived system to explore basic biological responses to MUC5B, the R33 phase of the proposal will test these findings in three established strains of mice (CCSP-Muc5bTg, SPC-Muc5bTg, and Muc5b-/- mice).基于对IPF和MUC5B的了解，我们假设慢性粘液过度分泌会损害粘膜纤毛运输，并导致持续的细胞损伤，导致宿主防御和过度修复并导致纤维增生性肺部疾病的发展。