Syndromic biliary atresia is a cholangiopathy characterized by fibro-obliterative changes in the extrahepatic bile duct (EHBD) and congenital malformations including laterality defects. The etiology remains elusive and faithful animal models are lacking. Genetic syndromes provide important clues regarding the pathogenic mechanisms underlying the disease. We investigated the role of the gene in the pathophysiology of syndromic biliary atresia. Constitutive and conditional knockout mice were generated to explore genetic pathology as a cause of syndromic biliary atresia. We investigated congenital malformations, EHBD and liver pathology, EHBD gene expression, and biliary epithelial cell turnover. Biliary drainage was functionally assessed with cholangiography. Histology and serum chemistries were assessed after DDC (3,5-diethoxycarbony l-1,4-dihydrocollidine) diet treatment and inhibition of the ciliary signaling effector GLI1. -deficient mice exhibited congenital anomalies including malrotation and heterotaxy. -deficient EHBDs were hypertrophic and fibrotic. -deficient EHBDs were patent but displayed delayed biliary drainage. -deficient livers exhibited ductular reaction and periportal fibrosis. After DDC treatment, -deficient mice exhibited EHBD obstruction and advanced liver fibrosis. -deficient mice had increased expression of fibrosis and extracellular matrix remodeling genes , , , , , , and ) and decreased expression of genes mediating ciliary signaling (, , , and ). Primary cilia were reduced on biliary epithelial cells and altered expression of ciliogenesis genes occurred in -deficient mice. Small molecule inhibition of the ciliary signaling effector GLI1 with Gant61 recapitulated -deficiency. loss causes both laterality defects and fibro-proliferative EHBD transformation through disrupted ciliary signaling, phenocopying syndromic biliary atresia. -deficient mice function as an authentic genetic model for study of the pathogenesis of biliary atresia. The syndromic form of biliary atresia is characterized by fibro-obliteration of extrahepatic bile ducts and is often accompanied by laterality defects. The etiology is unknown, but was identified as a potential genetic candidate for syndromic biliary atresia. We found that loss of the ciliary gene contributes to hepatobiliary pathology in biliary atresia, exhibited by bile duct hypertrophy, reduced biliary drainage, and liver fibrosis in -deficient mice. -deficient mice serve as a genetic model of biliary atresia and reveal ciliopathy as an etiology of biliary atresia. This model will help scientists uncover new therapeutic approaches for patients with biliary atresia, while pediatric hepatologists should validate the diagnostic utility of variants.

中文翻译：

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Pkd1l1 缺陷通过胆道上皮细胞的纤毛功能障碍驱动胆道闭锁

综合征性胆道闭锁是一种胆管病，其特征是肝外胆管 (EHBD) 的纤维闭塞性改变和先天性畸形，包括偏侧性缺陷。其病因仍然难以捉摸，并且缺乏可靠的动物模型。遗传综合征提供了有关疾病致病机制的重要线索。我们研究了该基因在综合征性胆道闭锁病理生理学中的作用。产生组成型和条件性基因敲除小鼠，以探索胆道闭锁综合征的遗传病理学原因。我们研究了先天性畸形、EHBD 和肝脏病理学、EHBD 基因表达和胆道上皮细胞更新。通过胆管造影对胆道引流进行功能评估。在 DDC（3,5-二乙氧基羰基 l-1,4-二氢可力丁）饮食治疗和抑制纤毛信号效应器 GLI1 后，对组织学和血清化学进行评估。 -缺陷小鼠表现出先天性异常，包括旋转不良和异位。 -EHBD 缺陷导致肥厚和纤维化。 - EHBD 缺陷是明显的，但表现出胆汁引流延迟。 -缺陷肝脏表现出导管反应和门静脉周围纤维化。 DDC治疗后，β-缺陷小鼠表现出EHBD阻塞和晚期肝纤维化。 -缺陷小鼠的纤维化和细胞外基质重塑基因表达增加，，，，，，，，和），而介导纤毛信号传导的基因表达减少（，，，，和）。胆管上皮细胞上的初级纤毛减少，并且纤毛发生基因的表达发生改变。 Gant61 缺陷对纤毛信号传导效应器 GLI1 的小分子抑制作用。丢失会导致偏侧性缺陷和纤维增殖性 EHBD 转化（通过破坏纤毛信号传导、表型胆管闭锁综合征）。 -缺陷小鼠可作为研究胆道闭锁发病机制的真实遗传模型。胆道闭锁的综合征形式的特征是肝外胆管的纤维闭塞，并且通常伴有偏侧性缺陷。病因尚不清楚，但被确定为综合征性胆道闭锁的潜在遗传候选者。我们发现纤毛基因的缺失会导致胆道闭锁的肝胆病理学，表现为胆管肥大、胆汁引流减少和肝纤维化。 -缺陷小鼠作为胆道闭锁的遗传模型，并揭示纤毛病是胆道闭锁的病因。该模型将帮助科学家发现胆道闭锁患者的新治疗方法，而儿科肝病学家应验证变异的诊断效用。