Dysregulation of hypothalamic neuropeptides is associated with biliary hyperplasia

下丘脑神经肽失调与胆道增生有关

• 批准号: 9750757
• 负责人: Sharon DeMorrow
• 金额: $ 35.49万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750757
• 关键词: Adipose tissue; Affect; Appetite Stimulants; Applications Grants; Bile Acids; Biliary; Blood Circulation; Brain; Cells; Cholestasis; Chronic; Corticotropin-Releasing Hormone; Data; Deoxycholic Acid; Development; Disease; Eating; Energy Metabolism; Equilibrium; Event; Exhibits; Extrahepatic; Fibrosis; Glucocorticoids; Goals; Health; Hepatic Encephalopathy; Hormones; Human; Hyperplasia; Hypothalamic structure; Injury; Knowledge; Laboratories; Lead; Leptin; Ligation; Liver; Liver Fibrosis; Liver diseases; Mitotic; Modeling; Nervous System Physiology; Neuropeptides; Neurosecretory Systems; Obstruction; Output; Pathologic Processes; Pathology; Pathway interactions; Patients; Peptides; Peripheral; Play; Primary biliary cirrhosis; Production; Proliferating; Publishing; Research; Research Proposals; Rodent Model; Role; Serum; Signal Transduction; Sphingosine-1-Phosphate Receptor; Stomach; System; Testing; Work; allograft rejection; alpha-Melanocyte stimulating hormone; autocrine; base; bile duct; cholangiocyte; cholestatic liver disease; chronic liver disease; design; effective therapy; feeding; ghrelin; graft vs host disease; hypothalamic-pituitary-adrenal axis; in vivo; liver allograft; liver injury; neuroendocrine phenotype; neuropeptide Y; novel; paracrine; primary sclerosing cholangitis; response; therapeutic development; treatment strategy

Project Summary/Abstract     Cholangiocytes are the target cells in cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). During the course of these diseases, mitotically dormant cholangiocytes are stimulated to proliferate and then undergo ductopenia. Associated with these cholangiopathies is a dysregulation of various neuroendocrine factors derived from the hypothalamus and the acquisition of a neuroendocrine phenotype in cholangiocytes. Taken together, these events contribute to the autocrine and paracrine pathways that modulate the proliferative response of cholangiocytes as well as liver damage and fibrosis in cholestatic liver injury. We have previously shown that circulating neuropeptide Y (NPY) and corticoptropin releasing hormone (CRH) are altered in models of biliary proliferation. Furthermore, we have recently demonstrated that the hypothalamic-pituitary-adrenal axis (HPA) is dampened during extrahepatic biliary obstruction resulting in suppressed glucocorticoid levels. Reactivation of the HPA axis by hypothalamic administration of CRH suppresses the proliferative capacity of cholangiocytes after bile duct ligation (BDL), suggesting a broader concept of hypothalamic control over cholangiocyte proliferation. The objective of this proposal is to investigate mechanisms by which extrahepatic biliary obstruction regulates the peripheral and central expression and activity of orexigenic peptides, and the subsequent effects on cholangiocyte proliferation. Based upon strong preliminary data, we propose the novel central hypothesis that early release of bile acids into the serum as a result of cholestasis results in the suppression of ghrelin expression from the stomach and increased production of leptin from adipose tissue. This imbalance results in the subsequent suppression of NPY and increase in αmelanocyte stimulating hormone (αMSH) expression in the hypothalamus, both of which are exacerbated by hypothalamic bile acid signaling. These peripheral and central changes in neuropeptide expression co-ordinately regulate cholangiocyte proliferation and biliary fibrosis. Our proposed work will focus on two specific aims that have been designed to test the following working hypotheses: 1) The imbalance between ghrelin and leptin during cholestasis is a result of aberrant bile acid signaling in the periphery and contributes to the resulting liver pathology; and 2) Hypothalamic NPY and αMSH are altered as a consequence of co-ordinate bile acid signaling in the hypothalamus and alterations in the peripheral ghrelin/leptin balance. Dissecting the pathophysiological interactions between the brain and the liver during cholestatic liver diseases may lead to an enhanced understanding of the pathological processes and consequences of this particular type of liver disease. This knowledge may play a paramount role in the development of therapeutic strategies for the treatment of cholangiopathies.

项目概要/摘要   胆管细胞是胆汁淤积性肝病（例如原发性胆汁性肝硬化（PBC）和 原发性硬化性胆管炎（PSC） 在这些疾病的过程中，胆管细胞处于有丝分裂休眠状态。 被刺激增殖，然后发生胆管减少症。 来自下丘脑的各种神经内分泌因子的失调以及获得 总而言之，这些事件有助于自分泌和胆管细胞的神经内分泌表型。 调节胆管细胞增殖反应以及肝损伤的旁分泌途径 我们之前已经证明循环神经肽 Y (NPY) 和胆汁淤积性肝损伤中的纤维化。 此外，我们还发现促肾上腺皮质激素释放激素（CRH）在胆道增殖模型中发生了改变。 最近证明，下丘脑-垂体-肾上腺轴（HPA）在肝外 胆道阻塞导致下丘脑 HPA 轴重新激活。 CRH 的施用可抑制胆管结扎 (BDL) 后胆管细胞的增殖能力， 提出了下丘脑控制胆管细胞增殖的更广泛概念。 提议是研究肝外胆道梗阻调节外周和胆管的机制。 促食欲肽的中枢表达和活性以及对胆管细胞的后续影响 基于强有力的初步数据，我们提出了一个新的中心假设：早期释放。 由于胆汁淤积，胆汁酸进入血清，导致胃饥饿素表达受到抑制 胃和脂肪组织瘦素的产生增加，这种不平衡导致了随后的结果。 抑制 NPY 并增加 α 黑素细胞刺激素 (αMSH) 的表达 下丘脑，这两种情况都会因下丘脑胆汁酸信号传导而加剧。 神经肽表达的中心变化协调调节胆管细胞增殖和胆汁 我们提出的工作将集中于两个具体目标，旨在测试以下内容。 工作假设：1) 胆汁淤积期间生长素释放肽和瘦素之间的不平衡是胆汁异常的结果 外周酸信号传导并导致肝脏病理学；2) 下丘脑 NPY 和 αMSH 由于下丘脑协调胆汁酸信号传导和 外周生长素释放肽/瘦素平衡剖析大脑和大脑之间的病理生理相互作用。 胆汁淤积性肝病期间的肝脏可能会增强对病理过程的了解 这种特定类型的肝病的知识和后果可能在这一过程中发挥着至关重要的作用。 开发治疗胆管病的治疗策略。