Functional Genetics in Idiopathic Pulmonary Fibrosis

描述（由申请人提供）：本提案的总体目标是了解MUC5B失调如何导致纤维增生性肺疾病的发展。这种方法是基于最近的两项进展。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，无论是遗传因素还是其他因素。MUC5B启动子SNP rs35705950已在6项独立研究中被证实为IPF的风险变异（1-6），是家族性和散发性IPF发展的已知最强风险因子（每个等位基因的优势比为H 4-8），并且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，尽管我们的GWAS鉴定了3个已建立的（TERC， 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占发生IPF风险的约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患者(7)的MUC5B表达增强相关，MUC5B信息和蛋白在IPF的病理病变中表达（1,8），我们最近发现MUC5B缺陷小鼠对博来霉素和石棉纤维增殖模型都具有耐药性（见初步数据）。基于这些观察结果，我们推测MUC5B启动子SNP通过外周空域的慢性粘液高分泌和积聚使个体处于发生IPF的风险中，从而损害粘膜纤毛运输，导致支气管肺泡区粘液粘附，从而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MUC5B失调如何导致纤维增殖性肺病的发展。该提案的R21阶段将使用体外人类细胞衍生系统来探索MUC5B的基本生物学反应，而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。基于对IPF和MUC5B的了解，我们假设慢性粘液高分泌会损害粘膜纤毛运输，导致持续的细胞损伤，导致宿主防御受损和过度修复，导致纤维增生性肺病的发展。

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.