Regulation of Bile Duct Growth in Bile Duct Ligated Rats

胆管结扎大鼠胆管生长的调节

• 批准号: 8236156
• 负责人: Gianfranco D Alpini
• 金额: $ 28.13万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236156
• 关键词: Angiogenic Factor; Angiopoietins; Antibodies; Apoptotic; Applications Grants; Bile fluid; Biliary; Bilirubin; Biological Process; Cell Proliferation; Cells; Cholestasis; Chronic; Clinical Management; Data; Development; Drug Metabolic Detoxication; Endogenous Factors; Enzymes; Fibrosis; Follicle Stimulating Hormone; Foundations; Goals; Gonadotropin Hormone Releasing Hormone; Growth; Growth Factor; Health; Homeostasis; Hormones; Hyperplasia; Inflammation; Liver; Liver diseases; Luteinizing Hormone; Maintenance; Melatonin; Modification; Molecular; Mus; Neuropeptides; Neurosecretory Systems; Neurotransmitters; Pathogenesis; Pathway interactions; Patients; Pharmacologic Substance; Pineal gland; Preventive Intervention; Primary biliary cirrhosis; Proliferating; Rattus; Regulation; Research; Role; Serum; Signal Pathway; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Transaminases; VEGFA gene; Vascular Endothelial Growth Factor Receptor-2; Work; autocrine; base; bile duct; cholangiocyte; effective therapy; improved; in vivo; insight; liver hyperplasia; novel; overexpression; paracrine; prevent; primary sclerosing cholangitis; receptor; response; tool development; treatment strategy

DESCRIPTION (provided by applicant): Cholangiocytes are the target cells in cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), which are characterized by the damage and proliferation of these cells. Cholangiocyte proliferation is critical for the maintenance of the biliary mass and secretory function during the pathogenesis of these devastating liver diseases. Proliferating cholangiocytes serve as a neuroendocrine compartment during the progression of liver diseases, and as such secrete a number of growth factors, and respond to hormones, neurotransmitters and neuropeptides contributing to the autocrine and paracrine pathways that modulate liver inflammation and fibrosis. The overall objective of this proposal is to determine the molecular mechanisms by which local (from cholangiocytes), paracrine (by administration of melatonin or anti-melatonin antibody) and central (from pineal gland) melatonin synthesis (regulated by the enzyme AANAT expressed in the liver mainly by cholangiocytes) participates in the homeostasis of the biliary mass during cholestasis and liver damage. We proposed the central hypothesis that local melatonin synthesis in cholangiocytes as well as central secretion of melatonin from the pineal gland (pineal gland/biliary axis) coordinately regulates biliary proliferation/damage during cholestasis. To test the central hypothesis, we have proposed two specific aims: (1) Evaluate the effects of the modulation of melatonin synthesis by pineal gland during cholestasis on cholangiocyte proliferation; and (2) Define the role of local melatonin synthesis in the regulation of the proliferation/damage of cholangiocytes to cholestasis. At the completion of this project, we expect to have determined the extent to which proliferation of cholangiocytes is regulated by central and local melatonin synthesis, and to have identified key signaling pathways by which melatonin regulates biliary proliferation/damage. The information gained from the successful completion of these studies are expected to provide important insights into the intracellular mechanisms regulating cholangiocyte proliferation, which will ultimately help in the identification of specific factors and pathways that can be targeted for the development of therapeutic interventions. Finally, results of these studies may impact the development of improved therapeutic strategies (targeting AANAT) for the treatment of chronic cholestatic liver diseases. PUBLIC HEALTH RELEVANCE: The health relatedness of this grant proposal 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 (cholangiopathies) cause proliferation/damage of bile ducts inside 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 the progressive mechanisms of cholestatic liver diseases, and increase opportunities for the development of novel treatment paradigms for the management of chronic liver diseases.

描述（由申请人提供）：胆管细胞是胆固性肝病中的靶细胞，例如原发性胆道肝硬化（PBC）和原发性硬化性胆管炎（PSC），其特征在于这些细胞的损伤和增殖。胆管细胞增殖对于在这些毁灭性肝病的发病机理期间维持胆道质量和分泌功能至关重要。肝病进展过程中增殖的胆管细胞充当神经内分泌室，因此分泌许多生长因子，并对激素，神经递质和神经肽反应，有助于自身分泌和侧核途径，从而调节脂肪炎症和纤维化。该提案的总体目的是确定分子机制，这些机制是局部（来自胆管细胞），旁分泌（通过褪黑激素或抗粘蛋白抗体的给药）和中心（来自松果腺）合成（由蛋白质腺苷）合成（由酶AANAT调控，在酶AANAT调控中，肝细胞主要由胆管细胞）参与胆汁淤积和肝脏损伤期间胆汁质量的体内平衡。我们提出了一个中心假设，即胆管细胞中的局部褪黑激素合成以及绿色腺（松果腺/胆道轴）共同调节胆汁脂蛋白过程中的胆汁增殖/损伤。为了检验中心假设，我们提出了两个具体的目的：（1）评估胆汁淤积过程中松果体对褪黑激素合成的调节对胆管细胞增殖的影响； （2）定义局部褪黑激素合成在调节胆管细胞增殖/损伤中的作用。该项目完成时，我们希望确定胆管细胞的增殖受中央和局部褪黑激素合成调节的程度，并确定了褪黑激素调节胆道增殖/损害的关键信号通路。从这些研究的成功完成中获得的信息有望提供有关调节胆管细胞增殖的细胞内机制的重要见解，这最终将有助于鉴定可以针对治疗干预措施发展的特定因素和途径。最后，这些研究的结果可能会影响改进的治疗策略（靶向AANAT）的发展，以治疗慢性胆汁淤积性肝病。 公共卫生相关性：该赠款提案的健康相关性是缺乏针对慢性胆固醇肝疾病的有效治疗方法，例如原发性胆汁肝硬化（PBC）和原发性硬化性胆管炎（PSC）。慢性胆汁淤积性肝病（胆管病）会导致肝内胆管的增殖/损害。我们研究的基本原理是，最终可以成功完成研究的促进机制，并增加了促进性肝疾病的渐进机制，并增加了开发新型治疗范式来治疗慢性肝病的机会。