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 MUC5B 失调如何导致纤维增生性肺病的发生。这种方法基于两项最新进展。首先，我们发现 MUC5B 是家族性和散发性特发性肺纤维化 (IPF) 的最强危险因素，包括遗传因素和其他因素。 MUC5B 启动子 SNP rs35705950 已在六项独立研究 (1-6) 中被验证为 IPF 的风险变异，是家族性和散发性 IPF 发展的最强已知风险因素（每个等位基因的比值比 H 4-8），并且代表在至少一半的家族性或散发性 IPF 病例中观察到的风险变异。 TERT 和 MUC5B）和 7 个新的肺纤维化位点 (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 约占发生 IPF 风险的 39%。其次，我们的研究结果表明 MUC5B 似乎参与了 IPF 的发病机制。 IPF 患者的 MUC5B 基因表达显着高于未受影响的受试者 (1)，MUC5B 启动子 SNP 与未受影响受试者 (1) 和 IPF 患者中 MUC5B 表达增强相关 (7)，MUC5B 信息和蛋白在 IPF 的病理病变中表达 (1, 8)，而且我们最近发现 Muc5b 缺陷小鼠对博来霉素和 纤维增殖的石棉模型（参见初步数据）。基于这些观察结果，我们推测 MUC5B 启动子 SNP 通过慢性粘液过度分泌和在周围空域的积累而使个体处于发生 IPF 的风险，从而损害粘液纤毛运输，导致支气管肺泡区域粘液粘附，从而诱发和加剧慢性炎症和损伤 (1, 10)。 我们设计了一种有效的分层方法来了解 MUC5B 失调如何导致纤维增生性肺病的发生。虽然该提案的 R21 阶段将使用体外人类细胞衍生系统来探索对 MUC5B 的基本生物反应，但该提案的 R33 阶段将在三种已建立的小鼠品系（CCSP-Muc5bTg、SPC-Muc5bTg 和 Muc5b-/- 小鼠）中测试这些发现。根据对 IPF 和 MUC5B 的了解，我们假设慢性粘液分泌过多会损害粘液纤毛运输并导致持续的细胞损伤，从而导致宿主防御受损和过度修复，并导致纤维增殖性肺病的发展。