Dysregulated Hypothalamic-pituitary-adrenal Axis During Biliary Hyperplasia

描述（由申请人提供）：胆汁淤积性肝病，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。以前的报告也表明，在这些疾病中，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。我们已经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轴活性受到抑制，这可能有助于在胆汁淤积早期阶段观察到的胆管细胞生长。该提案的总体目标是确定胆汁淤积性肝病对大脑的后果，更具体地说，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，我们提出了一个新的中心假设，胆汁淤积期间血清中积累的胆汁酸负责抑制HPA轴，随后循环糖皮质激素水平的降低对胆管细胞增殖有影响。我们提出的工作将侧重于三个具体目标，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，（二）胆汁淤积期间血清胆汁酸在脑中积聚，随后通过胆汁酸转运蛋白特异性摄取胆汁酸进入特定的神经元而抑制HPA轴。脑区和随后的糖皮质激素受体的激活，和（3）通过促肾上腺皮质激素释放激素的中枢给药的HPA轴的再激活有效地抑制了胆汁淤积期间所见的胆管细胞生长，这是通过糖皮质激素受体介导的AP-1和NF κ B转录活性的抑制。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会导致对这种特定类型肝病的病理过程和后果的增强理解。这方面的知识可能发挥至关重要的作用，在发展的治疗策略，治疗胆管疾病。

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.