The role of hypothalamic neuropeptides on biliary function during cholestasis

描述(由申请人提供)： 摘要：胆管细胞是原发性胆汁性肝硬变(PBC)、原发性硬化性胆管炎(PSC)等淤胆性肝病的靶细胞。在这些疾病的过程中，有丝分裂休眠的胆管细胞被刺激增殖，然后受到破坏。与这些胆管病相关的是来自下丘脑的各种神经内分泌因子的失调和胆管细胞神经内分泌表型的获得。综上所述，这些事件有助于调节胆管细胞的增殖反应的自分泌和旁分泌途径，以及在淤胆性肝损伤中的肝损伤和纤维化。我们之前已经证明，循环神经肽Y， 促肾上腺皮质激素释放激素(CRH)在胆管增生模型中发生改变。此外，我们最近证明，在肝外胆道梗阻时，下丘脑-垂体-肾上腺轴受到抑制，导致糖皮质激素水平受到抑制，下丘脑给予CRH重新激活HPA轴可抑制胆管结扎(BDL)后胆管细胞的增殖能力，这表明下丘脑控制胆管细胞增殖的概念更广泛。本研究的目的是探讨胆汁淤积调节下丘脑肽甘丙素表达的机制，以及这种改变对胆管细胞增殖的影响。基于强大的初步数据，我们提出了一个新的中心假设，即在胆汁淤积期间在血清中积累的胆汁酸是导致下丘脑和循环中甘丙素水平升高的原因，甘丙素的中枢和外周效应协调调节胆管细胞的增殖。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)在胆汁淤积性肝病期间，下丘脑肽Galanin的表达上调，并激活生长激素释放激素(GHRH)/生长激素(GH)轴以诱导胆管细胞增殖；(2)在实验性胆汁淤积期间，循环中的Galanin水平增加，并可直接作用于胆管细胞以诱导增殖；(3)下丘脑中Galanin的表达变化是下丘脑胆汁酸作用的直接结果。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。

DESCRIPTION (provided by applicant): 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 are damaged. 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, and corticoptropin releasing hormone (CRH) are altered in models of biliary proliferation. Furthermore, we have recently demonstrated that the hypothalamic-pituitary-adrenal axis is dampened resulting in suppressed glucocorticoid levels during extrahepatic biliary obstruction and that 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 of cholangiocyte proliferation. The objective of this proposal is to investigate mechanisms by which cholestasis regulates the expression of the hypothalamic peptide galanin and the subsequent effects of this altered response 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 increased hypothalamic and circulating galanin levels and that the central and peripheral effects of galanin co-ordinately regulate cholangiocyte proliferation. Our proposed work will focus on three specific aims that have been designed to test the following working hypotheses: (1) The expression of the hypothalamic peptide galanin is upregulated during cholestatic liver diseases and activates the growth hormone releasing hormone (GHRH) /growth hormone (GH) axis to induce cholangiocyte proliferation, (2) Circulating levels of galanin are increased during experimental cholestasis and can act on cholangiocytes directly to induce proliferation, and (3) The alteration of the galanin expression in the hypothalamus is a direct result of the actions of bile acids in th hypothalamus. 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.