Role of Mechanosensitive Receptors During Biliary Proliferation and Fibrosis

机械敏感受体在胆道增殖和纤维化过程中的作用

• 批准号: 8544056
• 负责人: Shannon Stroud Glaser
• 金额: --
• 依托单位: OLIN TEAGUE VETERANS CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544056
• 关键词: Acetylcholine; Acetylcholinesterase; Agonist; Alcohols; American; Applications Grants; Attenuated; Biliary; Butyrylcholinesterase; Cell physiology; Chemosensitization; Chronic; Chronic Hepatitis C; Collagen; Data; Development; Disease; Disease Progression; Epithelial Cells; Epithelium; Exposure to; Family; Family member; Fibronectins; Fibrosis; Gelatinase A; Gelatinase B; Genes; Growth; Health; Hepatitis Viruses; Hepatobiliary; Hospitalization; Incidence; Inflammation; Injury; Knockout Mice; Lead; Ligands; Link; Liver; Liver Fibrosis; Liver diseases; Maintenance; Mechanical Stress; Mechanics; Mediating; MicroRNAs; Molecular; Morbidity - disease rate; Mus; Nicotine; Nicotinic Receptors; Pathogenesis; Pathway interactions; Patients; Phenotype; Primary biliary cirrhosis; Role; Signal Transduction; Small Interfering RNA; Smooth Muscle Actin Staining Method; Stimulus; Testing; Tissues; Tobacco use; Transforming Growth Factors; United States Department of Veterans Affairs; Veterans; Work; autocrine; base; bile duct; biliary tract; body system; cholangiocyte; chronic liver disease; cigarette smoking; design; effective therapy; extracellular; high risk; in vitro testing; in vivo; locked nucleic acid; mortality; non-alcoholic fatty liver; novel; novel therapeutic intervention; paracrine; primary sclerosing cholangitis; programs; public health relevance; receptor; response

DESCRIPTION (provided by applicant): Cholangiocyte growth and remodeling are critical for the maintenance of biliary mass and secretory function during the pathogenesis of chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Cholangiocytes, the epithelia lining the biliary system, participate in a diverse array of cellular processes. In cholestatic livr diseases, cholangiocytes, through the products of their cellular activation, are implicated as the key link between bile duct injury and the subepithelial fibrosis that characterizes chronic hepatobiliary injury. Targeting specific factors that respond to the mechanical stress resulting from tissue injury may help limit inflammation and fibrosis that occur in hepatobiliary damages and diseases such as PBC, PSC and liver fibrosis. Emerging evidence indicates that exposure to cigarette smoke may stimulate the progression of chronic liver disease towards fibrosis such as PSC, PBC, chronic hepatitis C, and non-alcoholic fatty liver disease. Although mechanical stress such as occurs with biliary distention (commonly observed in PSC) and tobacco use (accelerates fibrosis in patients with PBC) activate cholangiocytes, the cellular and molecular mechanisms responsible for this phenotype remain unclear. The ¿7-nicotinic acetylcholine receptor (¿7-nAChR) mediates the proliferative and fibrogenic effects of nicotine and can also be activated by mechanical stress. We propose the overall hypothesis that ¿7-nAChR activation is a key and common pathway responsible for mediating the profibrogenic cholangiocyte phenotype. This postulate will be tested in three Specific Aims, which will determine whether (i) ligand-dependent activation of ¿7-nAChR during mechanical stress induces a profibrogenic phenotype via enhanced expression of miR-181 and -200; (ii) activation of mechanosensitive ¿7-nAChR stimulates Ca2+-dependent ACh secretion and miR-181 and -200 expression; and (iii) inhibition of ¿7-nAChR attenuates the activated biliary phenotype and fibrosis in vivo in cholestatic BDL mice. Completion of proposed studies will provide a framework for understanding how mechanical stimuli trigger local and systemic responses mediate hepatobiliary fibrosis. The findings will likely lead to new therapeutic approaches for cholestatic liver diseases and a reduction of morbidity and mortality in American Veterans with liver diseases.

描述（由申请人提供）： 胆管细胞的生长和重塑对于在慢性胆汁淤积性肝病（例如原发性胆道肝硬化（PBC））和一级硬化性胆管炎（PSC）的发病机理期间维持胆道质量和分泌功能至关重要。胆管细胞是胆道系统的上皮细胞，参与了潜水员的细胞过程。在胆固性LIVR疾病中，通过其细胞激活的产物，胆管细胞被实现为胆管损伤与表征慢性肝损伤的上皮下纤维化之间的关键联系。针对应对组织损伤引起的机械应力的特定因素可能有助于限制肝胆管损伤和疾病（例如PBC，PSC和肝纤维化）中发生的感染和纤维化。新兴的证据表明，尽管机械应力，例如PSC，PBC，PBC，慢性丙型肝炎和非酒精性脂肪肝脏疾病，但暴露于香烟烟雾可能会刺激慢性肝病的进展。尽管胆道延伸（通常在PSC中观察到）和烟草使用（加速PBC患者的纤维化）会激活胆管细胞，但导致这种表型的细胞和分子机制仍不清楚。 7-新生素乙酰胆碱受体（7-NACHR）介导了尼古丁的增殖和纤维化作用，也可以通过机械应力激活。我们提出了一个总体假设，即7-NACHR激活是负责介导纤维化胆管细胞表型的关键和常见途径。该假设将以三个特定的目的进行测试，这将确定（i）在机械应力期间配体依赖性的7-nACHR是否通过增强miR-181和-200的表达来诱导纤维化表型。 （ii）机械应力的激活»7-NACHR刺激Ca2+依赖性ACH分泌以及miR-181和-200表达； （iii）抑制€7-NACHR会减弱胆固醇BDL小鼠体内活化的胆道表型和纤维化。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局部和全身反应介导肝纤维化。这些发现可能会导致胆汁淤积的新治疗方法 肝疾病以及肝病美国退伍军人的发病率和死亡率的降低。