Autocrine/Paracrine Regulation of Intrahepatic Bile Duct Growth

胆管细胞是慢性淤胆性肝病如原发性胆管疾病的靶细胞 肝硬变(PBC)和原发性硬化性胆管炎(PSC)，其特征是损害/ 不同大小和功能的胆管细胞的增殖。胆管细胞增殖和 再生长对胆道肿块的维持和功能恢复至关重要。 这些胆管病的发病机制。细胞内调控机制的阐明 大小胆管对胆汁淤积的增殖/再生反应将发挥关键作用。 在胆汁淤积性肝病的治疗策略发展中的作用。 促胰液素(SEC)是一种胃肠激素，对肝胆的生长和再生至关重要。AS 促胰液素受体(SR)只在肝脏的胆管细胞中表达，在肝脏中的环磷酸腺苷水平 注射促胰液素后，胆管增多，富含碳酸氢盐的胆汁被分泌出来。在.期间 肝胆生长/损伤，胆管细胞获得神经内分泌表型，从而 分泌和响应神经内分泌激素，如血管内皮生长因子/神经生长因子和分泌素，调节 胆道肿块和损伤反应。针对在以下期间激活/停用的特定因素 肝损伤可能有助于限制胆道损伤以及PBC、PSC和肝纤维化的进展。我们有 研究表明，SEC/SR轴(仅由胆管细胞表达)调节胆管内的胆汁质量 结扎组(BDL)。胰泌素水平在BDL的早期阶段升高。缺乏SR表达 导致：(I)在BDL期间消融胆管生长；以及(Ii)相应地加重胆管损伤 毒素表明SEC是促增殖/保护因子。监管的机制 急性(短期BDL和CCl4给药)和慢性胆道模型中的SEC/SR轴 (PSC和PBC的动物模型)损伤尚不清楚。初步数据显示：(I) SEC/SR轴在胆管损伤过程中具有促增殖和保护作用(例如，CCl4 给药和dnTGFbetaRII KO小鼠)；(Ii)激活SEC/SR轴(增加 胆汁生长)导致miRNAs，let-7a和miR125-b下调，这两个miRNAs调节 血管内皮生长因子和神经生长因子等潜在靶基因的表达 和(Iii)PBC和PSC患者血清SEC水平降低，表明PBC和PSC患者血清SEC水平降低。 SEC/SR轴的失调可能是这些胆管病发病机制中的关键。我们 提出SEC/SR轴是负责中介的关键途径的总体假设 肝病时胆管的增殖/损害。我们的长期目标是定义治疗 SEC/SR轴在PBC/PSC等肝胆疾病中的作用总体假设是 通过三个具体目标进行评估。首先，我们将演示SEC/SR轴调制 急性胆汁淤积症动物模型中胆管细胞的增殖和损伤 激活自分泌/旁分泌机制。其次，我们将确定功能依赖于SEC MiRNAs参与促增殖/保护基因表达水平的调控 神经内分泌因素。第三，我们将确定营养/保护性SEC/SR轴 对PSC和PBC动物模型慢性胆汁淤积时胆管损伤/恢复的影响。治疗性的 促胰液素依赖基因/miRNA操作对胆管细胞生长和增殖的影响 已评估。对分子和功能的生理作用和机制的新见解 将获得人胆管上皮中的促胰液素信号。与此同时，根本的 在胆管树的生长、增殖和凋亡的调控方面获得的知识是可取的 推进胆道生物学/病理生理学领域的发展。 好了！

Cholangiocytes are the target cells in chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), which are characterized by the damage/ proliferation of cholangiocytes of different sizes and function. Cholangiocyte proliferation and regrowth are critical for the maintenance of biliary mass and the functional recovery during the pathogenesis of these cholangiopathies. The elucidation of the intracellular mechanisms regulating the proliferative/regenerative responses of large and small bile ducts to cholestasis will play a pivotal role in the development of therapeutic strategies for the treatment of cholestatic liver diseases. Secretin (SEC), a gastrointestinal hormone, is critical for hepatobiliary growth and regeneration. As the secretin receptor (SR) is only expressed by cholangiocytes in the liver, levels of cyclic-AMP in the bile ducts increase and bicarbonate rich bile is secreted after administration of secretin. During hepatobiliary growth/damage, cholangiocytes acquire neuroendocrine phenotypes and thereby secrete and respond to neuroendocrine hormones such as VEGF/NGF and secretin that regulate biliary mass and response to damage. Targeting specific factors that are activated/deactivated during liver injury may help limit biliary damage and the progression of PBC, PSC and liver fibrosis. We have shown that SEC/SR (expressed only by cholangiocytes) axis regulate biliary mass during bile duct ligation (BDL). Secretin levels are elevated during the early stages of BDL. Lack of SR expression leads to: (i) ablation of biliary growth during BDL; and (ii) exacerbation of biliary damage in response to toxins indicating that SEC is a pro-proliferative/protective factor. The mechanisms regulated by the SEC/SR axis during models of acute (short-term BDL and CCl4 administration) and chronic biliary damage (animal models of PSC and PBC) are unknown. Preliminary data indicate that: (i) the SEC/SR axis has pro-proliferative and protective functions during biliary injury (e.g., CCl4 administration and in dnTGFbetaRII KO mice); (ii) activation of the SEC/SR axis (which increases biliary growth) results in the downregulation of the miRNAs, let-7a and miR125-b, that modulate the expression of VEGF and nerve growth factor (NGF) as well as the other potential target genes such as Bcl-2; and (iii) the serum levels of SEC are reduced in PBC and PSC patients indicating that dysregulation of the SEC/SR axis may be key in the pathogenesis of these cholangiopathies. We propose the overall hypothesis that the SEC/SR axis is a key pathway responsible for mediating biliary proliferation/damage during liver diseases. Our long-term objective is to define the therapeutic role of the SEC/SR axis in hepatobiliary disorders such as PBC/PSC. The overall hypothesis will be evaluated by three specific aims. First, we will demonstrate that the SEC/SR axis modulates cholangiocyte proliferation and damage during animal models of acute cholestasis through the activation of autocrine/paracrine mechanisms. Second, we will identify functional SEC-dependent miRNAs involved in the regulation of the expression levels of the pro-proliferative/protective neuroendocrine factors. Third, we will determine the trophic/protective SEC/SR axis that contributes to biliary damage/recovery during chronic cholestasis in animal models of PSC and PBC. Therapeutic effects of secretin dependent gene/miRNA manipulation on biliary cell growth and proliferation will be evaluated. Novel insights into the physiological roles and mechanisms of molecular and functional secretin signaling in human biliary epithelium will be obtained. Meanwhile, the fundamental knowledge obtained in the regulation of growth, proliferation and apoptosis in biliary tree is expected to advance the field of biliary biology/ pathophysiology. !