Dysregulated Hypothalamic-pituitary-adrenal Axis During Biliary Hyperplasia

描述(申请人提供)：胆汁淤积性肝病，如原发性胆汁性肝硬变和原发性硬化性胆管炎，通常与血清胆汁酸浓度升高有关。以前的报告也表明，在这些疾病中，循环中的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的啮齿动物模型中，HPA轴的活性受到抑制，这可能有助于在胆汁淤积的早期阶段看到胆管细胞的生长。这项建议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。基于强大的初步数据，我们提出了一个新的中心假设，即在胆汁淤积过程中积累在血清中的胆汁酸是HPA轴受阻的原因，随后循环中糖皮质激素水平的下降对胆管细胞的增殖有影响。我们的工作将集中于三个特定的目标，旨在检验以下工作假说：(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)血清胆汁酸在胆汁淤积期间在大脑中积累，随后通过胆酸转运体将胆汁酸特异性摄取到特定脑区的神经元并随后激活糖皮质激素受体而抑制HPA轴；(3)中枢应用促肾上腺皮质激素释放激素重新激活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胆管细胞的生长。解剖胆汁淤积性肝病期间大脑和肝脏之间的病理生理相互作用可能有助于更好地理解这种特殊类型的肝病的病理过程和后果。这些知识可能在胆管病治疗策略的制定中起到至关重要的作用。 公共卫生相关性：该应用的健康相关性是缺乏对慢性淤胆性活动性疾病的有效治疗，例如原发性胆汁性肝硬化性胆管炎和原发性硬化性胆管炎。胆汁淤积性肝病通常与大脑功能受损有关，这会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提供对胆汁淤积性肝病进展的更多了解，并增加开发慢性肝病新治疗范例的机会。

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.