Growth Regulation of the Intrahepatic Biliary Tree

描述(申请人提供)：胆管细胞是慢性淤胆性肝病如原发性胆汁性肝硬变(PBC)、原发性硬化性胆管炎(PSC)的靶细胞，其特征是不同大小(即大小)的胆管细胞的损伤、增殖和分化。在这些破坏性肝病的发病过程中，胆管细胞分化和胆管重塑对于维持胆管质量和功能恢复至关重要。阐明大小胆管细胞对胆汁淤积和肝损伤/毒素的不同再生反应的细胞内机制，将对胆汁淤积性肝病的治疗策略的制定起到关键作用。在慢性肝胆损伤期间，一群具有双潜能的肝祖细胞被激活，以补充胆管细胞和肝细胞。如果人和啮齿动物的胆管中存在具有多潜能的小胆管细胞，这些细胞应该具有在肝损伤时分化为大胆管细胞或肝细胞的能力，例如大胆管细胞或肝细胞丢失或再生机制受阻的疾病条件。肝内胆管细胞的可塑性被认为是一种谱系的终末分化细胞可以直接分化为另一种谱系或进行转分化。因此，特定的细胞亚群，如表达已知胆管前体细胞标志的小胆管细胞，当暴露在特定的病理条件下时，可以假设包含一个多能细胞群。我们提出的中心假设是，小胆管细胞通过在疾病条件下获得肝祖细胞和大胆管细胞的表型来促进胆管损伤的恢复。在这一应用中，建议对具有治疗淤胆性肝损伤潜力的小胆管细胞的多潜能基因和microRNAs进行系统的研究。核心假设将通过三个具体目标进行评估。首先，我们将区分全能 大小胆管细胞中参与组织修复相关细胞功能的功能信号通路。其次，我们将鉴定依赖转化生长因子-�的miRNAs参与小胆管细胞分化/再生相关的细胞功能。最后，我们将在特定的动物模型中确定小胆管细胞及其相关miRNAs在促进转基因和慢性淤胆性肝损伤的形态和功能恢复方面的作用。细胞移植/miRNA操作对胆管细胞生长和分化的治疗效果将在体内进行评估。对人类胆管上皮细胞分子和功能异质性的生理作用和机制将获得新的见解。同时，在小胆管细胞/胆管定向祖细胞生长、分化和重塑的调控方面所获得的基础知识有望推动胆管细胞生物学/病理生理学领域的发展。

DESCRIPTION (provided by applicant): Cholangiocytes are the target cells in chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), which are characterized by the damage, proliferation and differentiation of cholangiocytes of different sizes (i.e., small and large). Cholangiocyte differentiation and biliar remodeling are critical for the maintenance of biliary mass and the functional recovery during the pathogenesis of these devastating liver diseases. The elucidation of the intracellular mechanisms regulating the differential regenerative responses of small and large cholangiocytes to cholestasis and liver injury/toxins will play a pivotal role in the development o therapeutic strategies for the treatment of cholestatic liver diseases. During chronic hepatobiliary injury, a population of bipotent liver progenitor cells becomes activated to replenis both cholangiocytes and hepatocytes. If small cholangiocytes with multipotential capacity exist within human and rodent bile ducts, these cells should possess the ability to differentiate into either large cholangiocytes or hepatocytes during liver damage, such as diseased conditions in which large cholangiocytes or hepatocytes are lost or regenerative mechanisms are hampered. The plasticity of intrahepatic cholangiocytes has been postulated that terminally differentiated cells of one lineage may directly differentiate into another lineage or undergo trans-differentiation. Therefore, specific subpopulations of cells, such as small cholangiocytes that express known biliary progenitor cell markers, can be hypothesized to contain a multipotent cell population when exposed to certain pathological conditions. We propose the central hypothesis that small cholangiocytes contribute to the recovery of biliary injury through acquiring the phenotypes of liver progenitor cells and large cholangiocytes under diseased conditions. Systematic investigation of pluripotent genes and microRNAs is proposed in this application as markers in small cholangiocytes with the therapeutic potentials for cholestatic liver injury. The central hypothesis will be evaluated by three specific aims. First, we will distinguish pluripotent functional signaling pathways involved in tissue repair-related cellular functions in small and large cholangiocytes. Second, we will identify TGF-� dependent miRNAs involved in differentiation/regeneration-related cellular functions in small cholangiocytes. Last, we will determine the effects of small cholangiocytes and their-associated miRNAs on accelerating the morphologic and functional recovery of transgenic and chronic cholestatic liver injury in specific animal models. Therapeutic effects of cell engraft/miRNA manipulation on biliary cell growth and differentiation will be evaluated in vivo. Novel insights into the physiological roles and mechanisms of molecular and functional heterogeneity in human biliary epithelium will be obtained. Meanwhile, the fundamental knowledge obtained in the regulation of growth, differentiation and remodeling by small cholangiocytes/biliary committed progenitors is expected to advance the field of cholangiocyte biology/ pathophysiology.