Growth Regulation of the Intrahepatic Biliary Tree

描述(申请人提供)：胆管细胞是一种简单的上皮细胞，排列在肝内和肝外胆管内，参与胆汁的产生。胆管细胞是慢性淤胆性肝病(胆管病)，如原发性胆汁性肝硬变、原发性硬化性胆管炎和胆管癌的损伤靶点。胆管疾病会导致发病率和死亡率，是导致肝移植的主要公共卫生问题。胆管病的特征是胆管细胞丢失，需要不同大小的胆管异质性生长以维持肝功能。阐明大小胆管细胞对胆汁淤积和肝损伤/毒素的不同增殖反应的细胞内机制，将对胆汁淤积性肝病的治疗策略的制定起到重要作用。最近，我们获得了新的初步数据，表明大小胆管细胞的增殖分别通过激活和/或抑制激活的T细胞核因子(NFAT)和cAMP反应元件结合蛋白(CREB)信号来不同地受钙和cAMP依赖的机制控制。基于我们的发现，我们提出了一个新的中心假设，即在副交感神经和交感神经以及胃泌素的刺激下，转录因子NFAT、CREB和可诱导的cAMP早期抑制因子(ICER)通过钙(NFAT和ICER)和cAMP依赖(CREB)信号机制的差异激活，调节胆汁淤积和肝损伤过程中大小胆管细胞的异质性增殖。为了验证这一假设，我们设计了三个特定的目标：(I)神经依赖的钙依赖转录因子NFAT的激活，通过激活分泌素受体(SR)和囊性纤维化跨膜调节因子(CFTR)来刺激小胆管细胞的增殖；(Ii)神经依赖的cAMP依赖的转录因子CREB的调节调节大胆管细胞的增殖；以及(Iii)胃肠激素胃泌素通过钙依赖的ICER表达激活来抑制胆汁淤积和胆管癌细胞生长过程中的大胆管细胞增殖。我们坚信，这些研究的结果将提供信息，不仅将使我们更好地了解胆管细胞的病理生物学，还将导致胆汁淤积性肝病的治疗。

DESCRIPTION (provided by applicant): Cholangiocytes are simple epithelia, which line the intrahepatic and extrahepatic bile ducts, and participate in the production of bile. Cholangiocytes are the targets of damage during chronic cholestatic liver diseases (cholangiopathies) such as primary biliary cirrhosis, primary sclerosing cholangitis, and cholangiocarcinoma. Cholangiopathies cause morbidity and mortality and are a major public health concern leading to liver transplantation. Cholangiopathies are characterized by cholangiocyte loss requiring the heterogeneous growth of different sized bile ducts for the maintenance of liver function. The elucidation of the intracellular mechanisms regulating the differential proliferative responses of small and large Cholangiocytes to cholestasis and liver injury/toxins will play an important role in the development of therapeutic strategies for the treatment of cholestatic liver diseases. Recently, we have obtained novel preliminary data demonstrating that small and large cholangiocyte proliferation is differentially controlled by calcium- and cAMP-dependent mechanisms via activation and/or inhibition of nuclear factor of activated T cells (NFAT) and cAMP- response-element-binding protein (CREB) signaling, respectively. Based upon our findings, we propose the novel central hypothesis that the differential activation of the transcription factors NFAT, CREB and inducible cAMP early represser (ICER, an inhibitory member of the CREB family), via calcium- (NFAT and ICER) and cAMP-dependent (CREB) signaling mechanisms stimulated by parasympathetic and sympathetic nerves and gastrin regulate the heterogeneous proliferation of small and large Cholangiocytes during cholestasis and liver injury. To test this hypothesis, we have designed three specific aims: (i) neural-dependent activation of the calcium-dependent transcription factor, NFAT, stimulates small cholangiocyte proliferation with activation of secretin receptor (SR) and cystic fibrosis transmembrane regulator (CFTR) expression; (ii) neural- dependent modulation of the cAMP-dependent transcription factor CREB regulates large cholangiocyte proliferation; and (iii) the gastrointestinal hormone gastrin inhibits large cholangiocyte proliferation during cholestasis and cholangiocarcinoma growth via calcium-dependent activation of ICER expression. It is our firm belief that the results of these studies will provide information that will not only allow us to better understand cholangiocyte pathobiology but will also lead to treatments for cholestatic liver diseases.