Neuroendocrine Regulation of Biliary Growth and Fibrosis

胆道生长和纤维化的神经内分泌调节

• 批准号: 9310481
• 负责人: Gianfranco D Alpini
• 金额: $ 28.99万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-02 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310481
• 关键词: Adenovirus Vector; Agonist; Applications Grants; Attenuated; Bile Duct Epithelium; Bile fluid; Biliary; Biological Process; Cells; Cholestasis; Chronic; Collagen; Cyclic AMP-Dependent Protein Kinases; Data; Data Analyses; Development; Disease; Drug Metabolic Detoxication; Epithelial Cells; Extrahepatic Cholestasis; FGF1 gene; Family; Fibronectins; Fibrosis; Foundations; Goals; Growth; HTR2A gene; Health; Hepatobiliary; In Vitro; Inflammation; Injury; Intervention; Ligation; Link; Liver; Liver Fibrosis; Liver diseases; Maintenance; Mechanical Stress; Mechanics; Mediating; Modification; Molecular; Neurosecretory Systems; Pathogenesis; Pathway interactions; Pharmacologic Substance; Pharmacology; Phenotype; Prevention; Primary biliary cirrhosis; Regulation; Research; Rodent Model; Role; Serotonin; Signal Pathway; Signal Transduction; Small Interfering RNA; Smooth Muscle Actin Staining Method; Stimulus; Testing; Therapeutic Agents; Tissues; Treatment Efficacy; Up-Regulation; Xenobiotics; autocrine; base; bile duct; cholangiocyte; chronic liver disease; effective therapy; genetic approach; in vivo; knock-down; liver injury; neuroendocrine phenotype; novel; overexpression; paracrine; primary sclerosing cholangitis; receptor; response; serotonin 5 receptor; serotonin receptor

In cholestatic liver diseases, cholangiocytes, through the secretion of neuroendocrine factors, are the key link between bile duct injury and the subepithelial fibrosis that characterizes chronic hepatobiliary injury. Targeting the factors that respond to the mechanical stress resulting from tissue injury may limit inflammation and liver fibrosis that occur in hepatobiliary damage and diseases such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and liver fibrosis. Although mechanical stress occurs with biliary distention (commonly observed in PSC and extrahepatic cholestasis) and activates cholangiocytes, the cellular and molecular mechanisms responsible for this activated neuroendocrine phenotypes remain unclear. While advances have been made to further our understanding of the paracrine and autocrine neuroendocrine factors that modulate biliary proliferation during cholestasis, unfortunately, viable therapies for management of cholangiopathies remain elusive. There remains, therefore, a critical need to understand the triggers of cholangiocyte growth and their responses to damage during cholestasis, which may help identify key signaling pathways that represent viable targets for the development of effective therapeutic agents. Preliminary data from the analysis of the activated neuroendocrine cholangiocyte phenotypes demonstrated that: (i) cholangiocytes express serotonin receptors (5-HTR) (2A, 2B and 2C); (ii) mechanical stress-dependent activation of 5-HTR2B stimulates 5-HT synthesis and secretion and an activated neuroendocrine cholangiocyte phenotype in a PKA and miR-16 mediated mechanism; (iii) activation of mechanosensitive 5-HTR2B signaling in concert with increased cholangiocyte expression and secretion of FGF1 (regulated by miR-16) stimulates biliary proliferation during in vitro mechanical stress and bile duct ligation (BDL). Based upon these findings, we propose the overall central hypothesis that the mechanosensitive 5-HTè5-HTR2A/BCèFGF1 signaling axis is a key pathway responsible for mediating the proliferative and profibrogenic cholangiocyte phenotype. This postulate will be tested in three specific aims, which will demonstrate that: (i) mechanical stress-dependent 5-HT synthesis and release induces an activated neuroendocrine and profibrogenic cholangiocyte phenotype mediated by activation of 5-HTR2A/B/C receptor family; (ii) FGF1 secretion by cholangiocytes during cholestasis mediates biliary proliferation and the activated neuroendocrine cholangiocyte phenotype in a 5-HTR2A/B/C receptor family and miR-16- dependent autocrine/paracrine mechanism; and (iii) inhibition of the 5-HTR2A/B/CèFGF1 axis attenuates the activated neuroendocrine biliary phenotype and fibrosis during cholestasis. Completion of proposed studies will provide a framework for understanding how mechanical stimuli trigger local and systemic responses mediate hepatobiliary fibrosis.

在胆固性肝病中，通过神经内分泌因子的分泌，胆管细胞是关键 胆管损伤与特征慢性肝损伤的下层纤维化之间的联系。 针对响应组织损伤导致的机械应力的因素可能会限制 在肝胆管损伤中发生的炎症和肝纤维化和诸如原发性胆道等疾病 肝硬化（PBC），原发性硬化性胆管炎（PSC）和肝纤维化。尽管机械应力发生 胆道距离（通常在PSC和e骨外胆汁淤积中观察到）并激活 胆管细胞，该激活神经内分泌的细胞和分子机制 表型仍然不清楚。尽管已经取得了进步来进一步了解我们对旁分泌的理解 不幸的是 可行的胆管病治疗疗法仍然难以捉摸。因此，仍然存在关键 需要了解胆管细胞生长的诱因及其对胆汁淤积期间损伤的反应， 这可能有助于确定代表可行目标开发的关键信号通路 有效的治疗剂。来自激活神经内分泌的分析的初步数据 胆管细胞表型表明：（i）胆管细胞表达5-羟色胺受体（5-HTR）（2a，2b 和2C）; （ii）5-HTR2B的机械应力依赖性激活刺激5-HT的合成和分泌，并且 PKA和miR-16介导的机制中活化的神经内分泌胆管细胞表型； （iii） 机械敏感的5-HTR2B信号传导的激活，随着胆管细胞的表达增加和 FGF1的分泌（由miR-16调节）在体外机械应力和 胆管连接（BDL）。基于这些发现，我们提出了总体中心假设 机械敏感的5-HTè5-htr2a/bcèfgf1信号轴是负责介导的关键途径 增殖和纤维化胆管细胞表型。该假设将以三个特定目的进行测试： 这将证明：（i）机械应力依赖性5-HT合成并释放会诱导 活化的神经内分泌和纤维化胆管细胞表型，通过5-HTR2A/B/C的激活介导 受体家族； （ii）胆汁淤积过程中胆管细胞分泌的FGF1分泌介导胆道增殖和 5-HTR2A/B/C受体家族中的活化神经内分泌胆管细胞表型和miR-16-- 依赖的自分泌/旁分泌机制； （iii）抑制5-Htr2a/b/cèfgf1轴可减弱 激活的神经内分泌胆道表型和纤维化期间的纤维化。拟议研究的完成 将提供一个框架，以了解机械刺激如何触发本地和全身响应 介导肝纤维纤维化。