Autocrine/Paracrine Regulation of Intrahepatic Bile Duct Growth

肝内胆管生长的自分泌/旁分泌调节

• 批准号: 8633852
• 负责人: Gianfranco D Alpini
• 金额: --
• 依托单位: OLIN TEAGUE VETERANS CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633852
• 关键词: Ablation; Acute; Alcohols; American; Animal Model; Apoptosis; Applications Grants; BCL2 gene; Bicarbonates; Bile fluid; Biliary; Biological Assay; Biology; Cell Proliferation; Cell Viability Process; Cells; Chemosensitization; Cholestasis; Chronic; Cirrhosis; Cyclic AMP; Data; Development; Disease; Disease Progression; Down-Regulation; Epithelium; Fibrosis; Functional disorder; Gastrointestinal Hormones; Gene Targeting; Genes; Growth; Health; Hepatitis Viruses; Hepatobiliary; Homeostasis; Hormones; Hospitalization; Human; Incidence; Inflammatory; Injury; Intrahepatic bile duct; Knowledge; Ligation; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Luciferases; Maintenance; Mediating; MicroRNAs; Modeling; Molecular; Mus; Natural regeneration; Nerve Growth Factors; Neurosecretory Systems; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiological; Play; Primary biliary cirrhosis; Recovery; Recovery of Function; Regulation; Role; Secretin; Serum; Signal Transduction; Staging; Testing; Therapeutic; Therapeutic Effect; Toxin; United States Department of Veterans Affairs; Vascular Endothelial Growth Factors; Veterans; Work; autocrine; base; bile duct; biliary tract; cell growth; cholangiocyte; chromatin immunoprecipitation; chronic liver disease; effective therapy; high risk; insight; liver injury; mortality; nanoparticle; novel; novel strategies; osmotic minipump; overexpression; paracrine; primary sclerosing cholangitis; public health relevance; receptor expression; regenerative; repaired; response; restoration; secretin receptor; therapeutic development; treatment strategy

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. !

胆管细胞是慢性胆汁淤积性肝疾病（例如原发性胆道）的靶细胞 肝硬化（PBC）和原发性硬化胆管炎（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 再生对于维持胆道质量和功能恢复至关重要 这些胆管病的发病机理。调节细胞内机制的阐明 大小胆管对胆汁淤积的增殖/再生反应将发挥关键性 在治疗胆固性肝病的治疗策略发展中的作用。 Sectionin（SEC）是一种胃肠道激素，对于肝胆管生长和再生至关重要。作为 Secralin受体（SR）仅由肝脏中的胆管细胞表达 胆汁导管增加，碳酸氢盐富胆胆分泌后分泌。期间 肝胆管生长/损害，胆管细胞获得神经内分泌表型，从而获得神经内分泌表型 分泌和回应神经内分泌激素，例如VEGF/NGF和Secritin 胆道质量和对损伤的反应。针对在此期间激活/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 表明SEC/SR（仅由胆管细胞表示）轴调节胆管期间胆汁质量 连接（BDL）。在BDL的早期阶段，秘密素水平升高。缺乏SR表达 导致：（i）BDL期间的胆汁生长消融； （ii）加剧胆道损害的响应 毒素表明SEC是促成/保护因素。由 急性模型（短期BDL和CCL4给药）和慢性胆道的模型中的SEC/SR轴 损坏（PSC和PBC的动物模型）尚不清楚。初步数据表明：（i） SEC/SR轴在胆道损伤期间具有促生物和保护功能（例如CCL4 给药和dntgfbetarii ko小鼠）； （ii）激活SEC/SR轴（增加 胆道生长）导致miRNA，Let-7a和miR125-B的下调，以调节 VEGF和神经生长因子（NGF）以及其他潜在靶基因的表达 作为Bcl-2； （iii）PBC和PSC患者的SEC的血清水平降低，表明 SEC/SR轴的失调可能是这些胆管病的发病机理的关键。我们 提出总体假设，即SEC/SR轴是负责中介的关键途径 肝病期间的胆道增殖/损害。我们的长期目标是定义治疗性 SEC/SR轴在肝素疾病中的作用，例如PBC/PSC。总体假设将是 通过三个特定目标进行评估。首先，我们将证明SEC/SR轴调节 通过 自分泌/旁分泌机制的激活。其次，我们将确定功能性SEC依赖性 参与调节促增量/保护性表达水平的miRNA 神经内分泌因素。第三，我们将确定贡献贡献的营养/保护性SEC/SR轴 在PSC和PBC动物模型中，慢性胆汁淤积期间的胆道损伤/恢复。治疗性 分泌蛋白依赖蛋白的基因/miRNA操纵对胆道细胞生长和增殖的影响 评估。对分子和功能的生理作用和机制的新见解 将获得人类胆道上皮中的分泌素信号传导。同时，基本 预计在调节生长，增殖和凋亡中获得的知识是预计 推进胆道生物学/病理生理学领域。 呢