Dysregulated Hypothalamic-pituitary-adrenal Axis During Biliary Hyperplasia

胆道增生期间下丘脑-垂体-肾上腺轴失调

• 批准号: 7983687
• 负责人: Sharon DeMorrow
• 金额: $ 28.51万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7983687
• 关键词: Adrenal Glands; Adrenalectomy; Affect; Bile Acids; Biliary; Blood; Blood - brain barrier anatomy; Brain; Brain region; Cholestasis; Chronic; Corticotropin; Corticotropin-Releasing Hormone; Data; Development; Disease; Disease Progression; Drops; Exhibits; Extrahepatic; Glucocorticoid Receptor; Glucocorticoids; Goals; Health; Hepatic Encephalopathy; Hippocampus (Brain); Hormones; Hyperplasia; Hypothalamic structure; Knowledge; Laboratories; Lead; Life; Ligation; Liver; Liver diseases; Mediating; NCOA2 gene; Neurons; Neurosecretory Systems; Obstruction; Operative Surgical Procedures; Output; Pathologic Processes; Pituitary Gland; Pituitary Hormones; Pituitary-Adrenal System; Play; Primary biliary cirrhosis; Production; Proteins; Relative (related person); Reporting; Research; Rodent Model; Role; Serum; Signal Transduction; Staging; Steroid biosynthesis; Stream; Stress; Testing; Transcription Factor AP-1; Work; allograft rejection; base; bile acid transporter; bile duct; cholangiocyte; design; effective therapy; graft vs host disease; hypothalamic pituitary axis; hypothalamic-pituitary-adrenal axis; in vitro Model; liver allograft; novel; prevent; primary sclerosing cholangitis; public health relevance; response; therapeutic development; transcription factor; treatment strategy; uptake

DESCRIPTION (provided by applicant): Cholestatic liver diseases such as primary biliary cirrhosis and primary sclerosing cholangitis are often associated with increased serum bile acid concentrations. Previous reports have also indicated a decrease in circulating glucocorticoid levels in these diseases. Glucocorticoid production and secretion are under the direct control of the hypothalamus-pituitary-adrenal (HPA) axis. We have obtained novel preliminary data indicating that there is a dampening of the HPA axis activity in our rodent model of cholestatis liver disease and that this may contribute to the cholangiocyte outgrowth seen in the early stages of cholestasis. The overall objective of this proposal is to determine the consequences of cholestatic liver disease on the brain and more specifically on the HPA axis and in turn determine the subsequent effects of a dampened HPA axis activity have on cholangiocyte proliferation. Based upon strong preliminary data, we propose the novel central hypothesis that the bile acids that accumulate in the serum during cholestasis are responsible for the dampening of the HPA axis and that the subsequent decrease in circulating glucocorticoid levels have implications on cholangiocyte proliferation. Our proposed work will focus on three specific aims that have been designed to test the following working hypotheses: (1) Decreased HPA axis activity is a consequence of cholestasis and contributes to the resulting increased cholangiocyte proliferation, (2) Serum bile acids accumulate in the brain during cholestasis and subsequently suppresses the HPA axis via the specific uptake of bile acids by bile acid transporters into neurons of particular brain regions and subsequent activation of glucocorticoid receptors, and (3) Reactivation of the HPA axis by central administration of corticotropin releasing hormone effectively inhibits the cholangiocyte outgrowth seen during cholestasis via the glucocorticoid receptor- mediated inhibition of AP-1 and NFkB transcriptional activity. 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 live disease. This knowledge may play a paramount role in the development of therapeutic strategies for the treatment of cholangiopathies. PUBLIC HEALTH RELEVANCE: The health relatedness of this application is that effective treatments are lacking for chronic cholestatic live diseases, such as primary biliary cirrhosis and primary sclerosing cholangitis. Cholestatic liver diseases are often associated with an impaired brain function that leads to dysregulated stress hormone control. 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 the opportunities for the development of novel treatment paradigms for chronic liver diseases.

描述（由申请人提供）：胆汁淤积性肝病，例如原发性胆汁性肝硬化和原发性硬化性胆管炎，通常与血清胆汁酸浓度升高相关。先前的报告还表明这些疾病中循环糖皮质激素水平下降。糖皮质激素的产生和分泌受下丘脑-垂体-肾上腺（HPA）轴的直接控制。我们获得了新的初步数据，表明在我们的胆汁淤积性肝病啮齿动物模型中，HPA 轴活性减弱，这可能有助于胆汁淤积早期阶段出现的胆管细胞生长。该提案的总体目标是确定胆汁淤积性肝病对大脑的影响，更具体地说是对 HPA 轴的影响，进而确定 HPA 轴活动减弱对胆管细胞增殖的后续影响。基于强有力的初步数据，我们提出了新的中心假设，即胆汁淤积期间血清中积累的胆汁酸导致 HPA 轴的抑制，并且随后循环糖皮质激素水平的降低对胆管细胞增殖有影响。我们提出的工作将集中于三个具体目标，旨在测试以下工作假设：(1) HPA 轴活性降低是胆汁淤积的结果，并导致胆管细胞增殖增加，(2) 血清胆汁酸在胆汁酸转运蛋白将胆汁酸特异性摄取到特定大脑区域的神经元中，随后激活糖皮质激素受体，从而抑制 HPA 轴，以及(3)通过中央施用促肾上腺皮质激素释放激素来重新激活HPA轴，通过糖皮质激素受体介导的AP-1和NFkB转录活性的抑制，有效地抑制胆汁淤积期间看到的胆管细胞生长。剖析胆汁淤积性肝病期间大脑和肝脏之间的病理生理学相互作用可能会加深对这种特定类型活体疾病的病理过程和后果的了解。这些知识可能在胆管病治疗策略的制定中发挥至关重要的作用。 公众健康相关性：本申请的健康相关性在于，慢性胆汁淤积性活体疾病（例如原发性胆汁性肝硬化和原发性硬化性胆管炎）缺乏有效的治疗方法。胆汁淤积性肝病通常与大脑功能受损有关，导致应激激素控制失调。我们研究的基本原理是，这些研究的成功完成最终有望加深对胆汁淤积性肝病进展的了解，并增加开发慢性肝病新型治疗模式的机会。