Regulation of Bile Ductular Proliferation

描述（由申请方提供）：以胆管上皮细胞（BDE）为靶点的胆汁淤积性疾病统称为“胆管病”。目前，唯一的治疗胆管疾病，熊去氧胆酸，是有效的，只有在改善生化标志物和延迟肝移植患者。没有针对胆管增殖的治疗，因为对健康和疾病中胆管增殖的理解很少。 最近，我们发现细胞外核苷酸通过P2Y核苷酸受体调节胆管增殖，并且阻断P2Y受体显著降低胆管增殖。这些发现得到了其他器官（如肺和肾）的补充。因此，通过细胞外核苷酸的信号传导是一个有吸引力的药理学目标，用于调节胆管增殖。 被称为核苷三磷酸二磷酸水解酶（NTPDases）的外核苷酸酶是P2Y活化和下游活性的关键调节剂。我们实验室最近的研究表明，外核苷酸酶NTPDase2（CD39L1）是BDE中P2Y受体激活的重要调节因子。NTPD酶2在称为门静脉成纤维细胞（PF）的肝门静脉区域内的独特肝成纤维细胞群中表达。我们实验室的初步数据表明，NTPDase2的功能，以调节胆管增殖。我们认为PF中NTPDase2的表达减弱了与胆管增生相关的BDE中P2Y受体的激活，并且这种调节在胆道纤维化中丢失。我们计划通过以下三个具体目标来验证这一假设：（1）确定细胞外核苷酸如何调节胆管增殖。(2)确定NTPDase2在胆管增殖调节中的作用。(3)确定正常和病变肝脏中NTPDase2表达的调节因子。 我们预计，这些拟议的实验结果将导致新的药理学方法的调节胆管增生的胆汁性肝硬化。

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.