Regulation of Bile Ductular Proliferation

描述(申请人提供)：以胆管上皮(BDE)为疾病靶点的胆汁淤积性疾病统称为“胆管病”。目前，治疗胆管病的唯一方法是熊去氧胆酸，它只在改善患者的生化标记物和推迟肝移植方面有效。目前还没有针对胆管增殖的治疗方法，因为人们对健康和疾病中胆管增殖的了解很少。 最近，我们发现细胞外核苷酸通过P2Y核苷酸受体调节胆管的增殖，阻断P2Y受体可显著抑制胆管的增殖。这些发现得到了其他器官的补充，如肺和肾脏。因此，通过细胞外核苷酸的信号转导是调节胆管增殖的一个有吸引力的药理靶点。 胞外核苷酸酶又称核苷三磷酸二磷酸水解酶(NTPDase)，是P2Y激活和下游活性的重要调节因子。我们实验室最近的研究表明，胞外核苷酸酶NTPDase2(CD39L1)是BDE中P2Y受体激活的重要调节因子。NTPDase2在肝门管区的一种独特的肝成纤维细胞群中表达，称为门脉成纤维细胞(PF)。我们实验室的初步数据表明，NTPDase2具有调节胆管增殖的作用。我们认为，在PF中表达NTPDase2可以减弱BDE中与胆管增殖有关的P2Y受体的激活，而这种调节在胆管纤维化中消失了。我们计划通过以下三个具体目标来检验这一假说：(1)确定细胞外核苷酸如何调控胆管增殖。(2)明确NTPDase2在胆管增殖调控中的作用。(3)确定正常肝脏和病变肝脏中NTPDase2表达的调控因素。 我们预计，这些拟议的实验结果将为调节胆汁性肝硬变的胆管增殖提供新的药理学方法。

DESCRIPTION (provided by applicant): Cholestatic conditions in which bile duct epithelia (BDE) are the target of disease are collectively known as "cholangiopathies". At present, the only treatment for cholangiopathies, ursodeoxycholic acid, is effective only at improving biochemical markers and delaying liver transplant in patients. No treatment has been directed toward bile ductular proliferation, because the understanding of bile ductular proliferation in health and disease is poorly understood. Recently, we have shown that extracellular nucleotides regulate bile ductular proliferation via P2Y nucleotide receptors, and that blockade of P2Y receptors markedly decreases bile ductular proliferation. These findings have been complemented by findings in other organs, such as the lungs and kidneys. Thus, signaling via extracellular nucleotides is an attractive pharmacologic target for regulation of bile ductular proliferation. Ecto-nucleotidases known as nucleoside triphosphate diphosphohydrolases (NTPDases) are critical regulators of P2Y activation and downstream activity. Recent studies from our laboratory have shown that the ecto-nucleotidase NTPDase2 (CD39L1) is an important regulator of P2Y receptor activation in BDE. NTPDase2 is expressed in a distinct liver fibroblastic cell population within the portal area of the liver known as portal fibroblasts (PF). Preliminary data from our laboratory suggest that NTPDase2 functions to regulate bile ductular proliferation. We propose that NTPDase2 expression in PF attenuates activation of P2Y receptors in BDE linked to bile ductular proliferation and that this regulation is lost in biliary fibrosis. We plan to test this hypothesis through the three following specific aims: (1) Determine how extracellular nucleotides regulate bile ductular proliferation. (2) Define the role of NTPDase2 in the regulation of bile ductular proliferation. (3) Identify factors regulating NTPDase2 expression in normal and diseased liver. We anticipate that the results of these proposed experiments will lead to novel pharmacologic approaches for the regulation of bile ductular proliferation in biliary cirrhosis.