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: 8277426
• 负责人: Sharon DeMorrow
• 金额: $ 20.71万
• 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/8277426
• 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; chronic liver disease; 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）：胆固性肝病，例如原发性胆汁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有关。先前的报告还表明，这些疾病中循环糖皮质激素水平降低。糖皮质激素的产生和分泌受到下丘脑 - 垂体 - 肾上腺（HPA）轴的直接控制。我们已经获得了新的初步数据，表明在啮齿动物肝肝病模型中，HPA轴活性受损，这可能有助于在胆汁淤积早期看到的胆管细胞生长。该提案的总体目的是确定胆汁淤积性肝病对大脑的后果，更具体地说是在HPA轴上，进而确定抑制HPA轴活动对胆管细胞增殖的后续影响。基于强大的初步数据，我们提出了一种新的中心假设，即胆汁淤积过程中累积在血清中的胆汁酸是导致HPA轴减弱的，并且随后循环糖皮质激素水平的降低在胆管细胞增殖上含有中隐含量。我们提出的工作将集中在旨在测试以下工作假设的三个特定目标上：（1）HPA轴活动的降低是胆汁淤积的结果，是胆汁淤积的结果，并有助于胆管胆汁脂蛋白增殖的增加，（2）血清胆汁酸在胆汁淤积过程中累积的脑酸酸中的酸性传播中的特异性酸液，并促进hpa酸的特异性糖尿病。特定大脑区域的神经元以及随后的糖皮质激素受体的激活，以及（3）通过中央给药的中心施用皮质激素释放激素来有效地抑制胆汁淤积的促胆管细胞的产物，从而通过葡萄皮层受体抑制了糖皮层受体的活性抑制了胆汁淤积的产物。在胆汁淤积性肝病期间剖析大脑与肝脏之间的病理生理相互作用可能会导致人们对这种特殊类型的活疾病的病理过程和后果有增强的理解。这些知识可能在治疗胆管疾病的治疗策略的发展中起着至关重要的作用。 公共卫生相关性：该应用的健康相关性是缺乏针对慢性胆汁淤积性疾病的有效治疗方法，例如原发性胆道肝硬化和原发性硬化性胆管炎。胆固性肝病通常与大脑功能受损相关，导致应激激素控制失调。我们研究的基本原理是，最终可以成功完成研究，以便对胆固性肝病的进展有更深入的了解，并增加开发新型慢性肝病治疗范式的机会。