Growth Regulation of the Intrahepatic Biliary Tree

描述（由申请人提供）：胆管细胞是单层上皮细胞，排列在肝内和肝外胆管上，参与胆汁的产生。胆管细胞是慢性胆汁淤积性肝病（胆管病）如原发性胆汁性肝硬化、原发性硬化性胆管炎和胆管癌损伤的目标。胆管病变可引起发病率和死亡率，是导致肝移植的主要公共卫生问题。胆管病变的特点是胆管细胞损失，需要不同大小的胆管异质生长来维持肝功能。阐明小胆管细胞和大胆管细胞对胆汁淤积和肝损伤/毒素的差异增殖反应的细胞内调节机制，将在制定治疗胆汁淤积性肝病的治疗策略中发挥重要作用。最近，我们获得了新的初步数据，表明小胆管细胞和大胆管细胞的增殖分别通过激活和/或抑制活化T细胞核因子（NFAT）和cAMP-反应元件结合蛋白（CREB）信号，受到钙和cAMP依赖机制的不同控制。基于我们的研究结果，我们提出了一个新的中心假设，即转录因子NFAT、CREB和诱导性cAMP早期抑制因子（ICER， CREB家族的抑制性成员）通过钙- （NFAT和ICER）和cAMP依赖（CREB）信号机制的差异激活，由副交感神经和交感神经和胃泌素刺激，调节胆汁淤滞和肝损伤期间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)钙依赖性转录因子NFAT的神经依赖性激活，通过激活分泌素受体（SR）和囊性纤维化跨膜调节因子（CFTR）的表达来刺激小胆管细胞增殖；（ii） camp依赖性转录因子CREB的神经依赖性调节大胆管细胞增殖；（iii）胃肠激素胃泌素通过钙依赖性激活ICER表达抑制胆汁淤积和胆管癌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，不仅使我们能够更好地了解胆管细胞病理生物学，而且还将导致治疗胆汁淤积性肝病。

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.