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Role of the Renin-Angiotensin System in the Regulation of Biliary Proliferation

肾素-血管紧张素系统在胆道增殖调节中的作用

基本信息

批准号：
7924196
负责人：
Shannon Stroud Glaser
金额：
$ 30.79万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7924196
关键词：
Angiotensin II Angiotensin-Converting Enzyme Inhibitors Angiotensins Biliary Binding Cardiac Cell Line Cholestasis Chronic Cirrhosis DTR gene Data Development Disease Disease Progression Disintegrins Epidermal Growth Factor Receptor Epithelial Cells Extracellular Matrix Extrahepatic Extrahepatic Cholestasis Fibrosis Focal Adhesion Kinase 1 G-Protein-Coupled Receptors Goals Health Hormones Human In Vitro Inflammation Integrins Knockout Mice Knowledge Laboratories Ligand Binding Ligands Ligation Liver Liver diseases MAP Kinase Gene Maintenance Mechanical Stress Mechanics Metalloproteases Molecular Conformation Morbidity - disease rate Neuropeptides Neurosecretory Systems Obstruction Pathogenesis Pathway interactions Peptidyl-Dipeptidase A Performance Play Primary biliary cirrhosis Production Proliferating Rattus Receptor, Angiotensin, Type 1 Regulation Renin-Angiotensin System Research Role Signal Pathway Signal Transduction Stress Testing Therapeutic Therapeutic Intervention Transactivation Work autocrine base bile duct cell type cholangiocyte design effective therapy experience heparin-binding EGF-like growth factor improved in vitro Model in vivo Model insight kinase inhibitor liver transplantation mortality mouse model novel paracrine primary sclerosing cholangitis programs public health relevance receptor response therapeutic development treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Human chronic cholestatic liver diseases (i.e., cholangiopathies) trigger the proliferation and damage of cholangiocytes that are the epithelial cells that line the biliary apparatus. These cholangiopathies cause morbidity and mortality and are a major reason for liver transplantation. During the progression of cholangiopathies, proliferation of cholangiocytes is critical for the maintenance of biliary mass and function. Proliferating cholangiocytes serve as a neuroendocrine compartment during liver disease pathogenesis and secrete and respond to hormones and neuropeptides, which contribute to the autocrine and paracrine pathways that modulate liver inflammation and biliary fibrosis associated with cholestatic liver diseases. The elucidation of the factors regulating the proliferative responses of cholangiocytes to cholestasis is critical for the development of therapeutic strategies for the treatment of cholestatic liver diseases. The overall objective of the current application is to determine the role that the local cholangiocyte renin-angiotensin-system (RAS) plays in the maintenance of biliary mass during cholestasis. We have recently obtained novel data indicating that cholangiocytes express a local RAS and that chronic administration of angiotensin II (Ang II) increases the proliferation of normal rat cholangiocytes and enhances the proliferation of cholangiocytes during extrahepatic cholestasis induced by bile duct ligation (BDL). We have also obtained unique in vitro preliminary data demonstrating that mechanical stress, which occurs during extrahepatic obstructive disorders, induces cholangiocyte proliferation via mechanical activation of the angiotensin type 1 receptor (AT1). Based on preliminary findings, we propose the novel central hypothesis that the RAS plays a key role in regulating biliary mass. As such, cholangiocyte proliferation during cholestasis is stimulated via ligand (Ang II)- and mechanical stress-dependent stimulation of the AT1 resulting in the activation of ERK1/2 MAPK pathway-dependent signaling mechanisms triggering activation of cholangiocyte proliferation and the local RAS via coordinated signaling of stress activated MAPKs JNK1/2 and p381. Our proposed work will focus on three specific aims designed to test the following working hypotheses: (i) activation of AT1 by the ligand Ang II plays a key role in the modulation of cholangiocyte proliferation; (ii) mechanical stress-induced activation of AT1 and the local RAS plays an unique role in the modulation of cholangiocytes proliferation; and (iii) ligand and mechanical activation of AT1 and the RAS plays a key regulatory role for controlling the proliferation of cholangiocytes during in vivo models of liver disease. Knowledge of the intracellular mechanisms through which the RAS modulates cholangiocyte proliferative responses to cholestasis will play an important role in the development of therapeutic strategies for the treatment of liver diseases (e.g., cirrhosis, PBC, PSC, and other ductopenic diseases). PUBLIC HEALTH RELEVANCE: The health relatedness of this application is that effective treatments are lacking for chronic cholestatic liver diseases, such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Chronic cholestatic liver diseases cause damage to the bile ducts of the liver. The rationale for our research is that the successful completion of the studies can ultimately be expected to provide a greater understanding of cholestatic liver disease progression and increase opportunities for the development of novel treatment paradigms for chronic liver diseases.

描述（由申请人提供）：人类慢性胆汁淤积性肝病（即胆管病）引发胆管细胞的增殖和损伤，胆管细胞是排列在胆管上的上皮细胞。这些胆管病变可引起发病率和死亡率，是肝移植的主要原因。在胆管疾病的发展过程中，胆管细胞的增殖对维持胆道质量和功能至关重要。在肝脏疾病发病过程中，增殖的胆管细胞作为神经内分泌室，分泌并响应激素和神经肽，这些激素和神经肽参与调节与胆汁淤积性肝病相关的肝脏炎症和胆道纤维化的自分泌和旁分泌途径。阐明调节胆管细胞对胆汁淤积增生反应的因素对于开发治疗胆汁淤积性肝病的治疗策略至关重要。当前应用的总体目标是确定局部胆管细胞肾素-血管紧张素系统（RAS）在胆汁淤积期间维持胆道肿块中的作用。我们最近获得了新的数据，表明胆管细胞表达局部RAS，并且在胆管结扎（BDL）引起的肝外胆汁淤滞期间，慢性给药血管紧张素II （Ang II）增加了正常大鼠胆管细胞的增殖，并增强了胆管细胞的增殖。我们还获得了独特的体外初步数据，证明肝外梗阻性疾病期间发生的机械应力通过血管紧张素1型受体（AT1）的机械激活诱导胆管细胞增殖。基于初步研究结果，我们提出RAS在调节胆道质量中起关键作用的新中心假设。因此，胆汁淤积期间的胆管细胞增殖是通过配体（Ang II）和机械应力依赖的AT1刺激来刺激的，从而激活ERK1/2 MAPK通路依赖的信号机制，通过应激激活的MAPKs JNK1/2和p381的协调信号触发胆管细胞增殖和局部RAS的激活。我们提出的工作将集中在三个特定的目标上，旨在测试以下工作假设：(i)配体Ang II激活AT1在调节胆管细胞增殖中起关键作用；（ii）机械应力诱导的AT1和局部RAS激活在调节胆管细胞增殖中起独特作用；（iii）在肝脏疾病的体内模型中，AT1和RAS的配体和机械激活对控制胆管细胞的增殖起着关键的调节作用。了解RAS通过细胞内机制调节胆管细胞对胆汁淤积的增殖反应，将在肝病（如肝硬化、PBC、PSC和其他导管减少性疾病）治疗策略的发展中发挥重要作用。公共卫生相关性：该应用与健康的相关性在于，慢性胆汁淤积性肝病，如原发性胆汁性肝硬化（PBC）和原发性硬化性胆管炎（PSC）缺乏有效的治疗方法。慢性胆汁淤积性肝病会损害肝脏的胆管。我们研究的基本原理是，这些研究的成功完成最终可以提供对胆汁淤积性肝病进展的更好理解，并为慢性肝病的新治疗模式的发展增加机会。