Genome-wide association studies have shown that a gene variant in the Family with Sequence Similarity 13, Member A (FAM13A) is strongly associated with reduced lung function and the appearance of respiratory symptoms in patients with Chronic Obstructive Pulmonary Disease (COPD). A key player in smoking-induced tissue injury and airway remodeling is the transforming growth factor β1 (TGFβ1). To determine the role of FAM13A in TGFβ1 signaling, FAM13A-/- airway epithelial cells were generated using CRISPR-Cas9, while over-expression of FAM13A was achieved using lipid nanoparticles. Wildtype (WT) and FAM13A-/- cells were treated with TGFβ1, followed by gene and/or protein expression analyses. FAM13A-/- cells augmented TGFβ1-induced increase in COL1A1 and MMP2 expression compared to WT cells. This effect was mediated by an increase in CTNNB1 expression in FAM13A-/- cells compared to WT cells after TGFβ1 treatment. FAM13A over-expression was partially protective from TGFβ1-induced COL1A1 expression. Finally, we showed that airway epithelial-specific FAM13A protein expression is significantly increased in patients with severe COPD compared to control non-smokers, and negatively correlated with lung function. In contrast, β-catenin (CTNNB1), which has previously been linked to be regulated by FAM13A, is decreased in the airway epithelium of smokers with COPD compared to non-COPD subjects. Together, our data showed that FAM13A may be protective from TGFβ1-induced fibrotic response in the airway epithelium via sequestering CTNNB1 from its regulation on downstream targets. Therapeutic increase in FAM13A expression in the airway epithelium of smokers at risk for COPD, and those with mild COPD, may reduce the extent of airway tissue remodeling.

中文翻译：

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FAM13A 作为调节 TGF-β 诱导的 COPD 气道组织重塑的潜在治疗靶点

全基因组关联研究表明，具有序列相似性 13 的家族成员 A (FAM13A) 中的基因变异与慢性阻塞性肺病 (COPD) 患者的肺功能降低和呼吸道症状的出现密切相关。吸烟引起的组织损伤和气道重塑的关键因素是转化生长因子 β1 (TGFβ1)。为了确定 FAM13A 在 TGFβ1 信号传导中的作用，使用 CRISPR-Cas9 生成 FAM13A-/- 气道上皮细胞，而使用脂质纳米颗粒实现 FAM13A 的过表达。野生型 (WT) 和 FAM13A-/- 细胞用 TGFβ1 处理，然后进行基因和/或蛋白质表达分析。与 WT 细胞相比，FAM13A-/- 细胞增强了 TGFβ1 诱导的 COL1A1 和 MMP2 表达增加。与 TGFβ1 处理后的 WT 细胞相比，FAM13A-/- 细胞中 CTNNB1 表达的增加介导了这种效应。FAM13A 过表达对 TGFβ1 诱导的 COL1A1 表达有部分保护作用。最后，我们发现与对照组的非吸烟者相比，重度 COPD 患者的气道上皮特异性 FAM13A 蛋白表达显着增加，并且与肺功能呈负相关。相比之下，与非 COPD 受试者相比，COPD 吸烟者气道上皮中的 β-连环蛋白 (CTNNB1) 先前被认为受 FAM13A 调节。总之，我们的数据表明，FAM13A 可能通过将 CTNNB1 与其对下游靶标的调节隔离开来保护气道上皮细胞免受 TGFβ1 诱导的纤维化反应。