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CFTR modulates innate immune response in biliary epithelium: Role in the pathogenesis and treatment of Cystic-Fibrosis-related liver disease.

CFTR 调节胆管上皮的先天免疫反应：在囊性纤维化相关肝病的发病机制和治疗中的作用。

基本信息

批准号：
10454325
负责人：
Mario Strazzabosco
金额：
$ 54.19万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2024-07-31
项目状态：
已结题

项目摘要

SUMMARY Cystic Fibrosis (CF) is a common and clinically severe genetic disease, caused by mutations in CFTR, a membrane protein that mediates chloride and fluid secretion in a number of secretory epithelia, including the biliary tree. Cystic Fibrosis liver disease (CFLD) is a chronic cholangiopathy that can eventually evolve into sclerosing cholangitis and focal biliary cirrhosis. The pathogenesis of this condition is not well understood and treatment is limited to the administration of choleretic bile acids, or in selected cases, liver transplantation. CFLD has been classically considered a consequence of the impaired bile secretion caused by the defective CFTR channel function. However, while biliary secretion is universally reduced in CF, the spontaneous development of CFLD is less frequent, suggesting that genetic and/or acquired factors are at play. Our previous studies suggested that reduced tolerance of the biliary innate immune system to endotoxins plays a major pathogenetic role in CFLD. We showed that cholangiocytes isolated from Cftr-KO mice have higher NF-κB activity and secrete a larger amount of inflammatory cytokines, when exposed to the TLR4-ligand LPS. We have also demonstrated that in CF-defective cholangiocytes, TLR4 is activated by the unrestrained function of Src family kinases (SFK), a consequence of defective CFTR. This mechanism is present also in cholangiocytes derived from human iPSC homozygous for the ΔF508 mutation. In addition, novel exciting preliminary data show that the gut microbiota in CFTR-KO mice is already different from WT littermates at birth and it is skewed towards the prevalence of a more pro-inflammatory flora. In this application we will test the hypothesis that CFLD may result from the combination of a genetic mutation affecting biliary epithelial innate immunity along with changes in microbiota composition and increased intestinal permeability. In particular, (1) we will use iPSC technology to dissect the impact of functionally different CFTR mutations on the mechanisms leading to a pro-inflammatory phenotype in human cholangiocytes and (2) we will study whether changes in the gut microbiota play a causal role in the development of liver disease in mouse models of CF. Our study will discover novel aspects of secretory epithelia physiology and innate immunity and clarity if changes in the gut microbiota play a possible causal role in CFLD. These studies represent a paradigm-shift in the understanding of the pathogenesis of CFLD and imply that treatment for CFLD should also control inflammation and the impact of the intestinal microbiota. The outcome of this project will lay the foundation for novel intervention strategies that will have an impact on the management of CFLD and other cholangiopathies. !

概括囊性纤维化 (CF) 是一种常见且临床严重的遗传性疾病，由 CFTR 突变引起，CFTR 是一种介导许多分泌上皮细胞中氯离子和液体分泌的膜蛋白，包括胆管树。囊性纤维化肝病 (CFLD) 是一种慢性胆管病，最终可能演变成硬化性胆管炎和局灶性胆汁性肝硬化。这种情况的发病机制尚不清楚，治疗仅限于使用利胆胆汁酸，或在某些情况下进行肝移植。 CFLD 传统上被认为是胆汁分泌受损的结果。 CFTR 通道功能有缺陷。然而，虽然 CF 患者胆汁分泌普遍减少， CFLD 自发发生的频率较低，这表明遗传和/或后天因素玩。我们之前的研究表明，胆道先天免疫系统对内毒素的耐受性降低在 CFLD 中起重要的致病作用。我们发现从 Cftr-KO 小鼠中分离的胆管细胞具有当暴露于 TLR4 配体时，NF-κB 活性更高并分泌大量炎症细胞因子脂多糖。我们还证明，在 CF 缺陷的胆管细胞中，TLR4 被不受限制的 Src 家族激酶 (SFK) 的功能，这是 CFTR 缺陷的结果。这种机制也存在于源自 ΔF508 突变纯合人 iPSC 的胆管细胞。此外，新颖精彩初步数据显示，CFTR-KO 小鼠的肠道微生物群在出生时就与 WT 同窝小鼠不同并且它倾向于更促炎菌群的流行。在此应用中，我们将检验 CFLD 可能由遗传因素组合导致的假设影响胆道上皮先天免疫的突变以及微生物群组成的变化和肠道通透性增加。特别是，（1）我们将使用 iPSC 技术来剖析以下因素的影响：功能上不同的 CFTR 突变导致人类促炎症表型的机制（2）我们将研究肠道微生物群的变化是否在胆管细胞中发挥因果作用 CF小鼠模型中肝病的发展。我们的研究将发现分泌上皮生理学和先天免疫的新方面，并且如果肠道微生物群的变化可能是 CFLD 的致病因素。这些研究代表了范式的转变加深对 CFLD 发病机制的了解，并暗示 CFLD 的治疗也应控制炎症和肠道微生物群的影响。该项目的成果将为将对 CFLD 和其他胆管病的治疗产生影响的新型干预策略。！