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）：本提案的总体目标是了解MUC 5 B失调如何导致纤维增生性肺病的发展。这一方法基于两项最新进展。首先，我们发现MUC 5 B是家族性和散发性特发性肺纤维化（IPF）的最强风险因素，无论是遗传还是其他因素。MUC 5 B启动子SNP rs35705950已在6项独立研究中被验证为IPF的风险变体（1-6），是家族性和散发性IPF发生的最强已知风险因素（每个等位基因的优势比H 4-8），代表了至少一半家族性或散发性IPF病例中观察到的风险变异。在研究了TERC、TERT和MUC 5 B基因座和7个新的肺纤维化基因座（5）后，MUC 5 B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占IPF发生风险的约39%。其次，我们的研究结果表明，MUC 5 B似乎参与了IPF的发病机制。IPF患者比未受影响的受试者具有显著更多的MUC 5 B基因表达（1），MUC 5 B启动子SNP与未受影响的受试者（1）和IPF患者（7）中增强的MUC 5 B表达相关，MUC 5 B信息和蛋白质在IPF的病理性病变中表达（1，8），我们最近发现Muc 5 b缺陷小鼠对博莱霉素和石棉纤维增生模型都有抗性（见初步数据）。基于这些观察结果，我们推测MUC 5 B启动子SNP使个体处于通过外周空气中的慢性粘液分泌过多和积累而发展IPF的风险中，这损害了粘液纤毛转运，导致支气管肺泡区域中的粘液粘附，并因此诱导和增强慢性炎症和损伤（1，10）。 我们设计了一种有效的分层方法来了解MUC 5 B失调如何导致纤维增生性肺病的发展。虽然该提案的R21阶段将使用体外人细胞衍生系统来探索对MUC 5 B的基本生物学反应，但该提案的R33阶段将在三种已建立的小鼠品系（CCSP-Muc 5 bTg，SPC-Muc 5 bTg和Muc 5 b-/-小鼠）中测试这些发现。基于对IPF和MUC 5 B的了解，我们假设慢性粘液分泌过多损害粘液纤毛转运，导致持续性细胞损伤，导致宿主防御受损和过度修复，并导致纤维增生性肺病的发展。