The role of CDK5 in cholangiocyte differentiation and morphogenesis

描述（由申请人提供）：构成肝脏胆汁转运（胆汁）网络的胆管细胞变性是肝衰竭的主要原因，约占所有肝移植患者的三分之一。虽然结构和 成熟网络的功能已被很好地表征，胆管发育和形态发生的过程还不清楚。这是特别相关的，因为大多数胆管病涉及分化的胆管细胞的损失。坂口实验室的初步研究已经确定细胞周期蛋白依赖性蛋白激酶5（CDK5）作为胆管细胞形态发生的调节剂，通过促进功能性胆管网络所需的细胞突起的生长。以前已经发现CDK5是发育过程中神经元投射形成调控的主要参与者，该项目将重点评估通过CDK5调控胆管细胞形态发生的已知途径的作用。了解调节胆管细胞分化和形态的机制将提供对胆管病中观察到的相反过程的深入了解，在胆管病中，预测收缩和分化丢失。这些信息将代表着治疗一类影响数千人且长期结果不佳的疾病的重要一步。 公共卫生相关性：胆道网络对于基本肝功能和胆管病（例如，原发性胆汁性肝硬化和原发性硬化性胆管炎）是慢性肝病的主要原因。本研究旨在确定胆道网络发展和维持其分化状态的机制，这是特别相关的，因为大多数已知的胆管病导致胆管细胞形态和分化的丧失。这项工作的目标是更好地了解胆管细胞的细胞生物学， 潜在的治疗靶点

DESCRIPTION (provided by applicant): Degeneration of the cholangiocytes that comprise the liver's bile transporting (biliary) network is a major cause of liver failure, and account for approximately one third of all patients referred for liver transplantation. While the structure and function of the mature network has been well-characterized, the process of biliary development and morphogenesis is not well understood. This is particularly relevant, as most cholangiopathies involve a loss of differentiated cholangiocytes. Preliminary studies in the sakaguchi lab have identified cyclin-dependent protein kinase 5 (CDK5) as a regulator of cholangiocyte morphogenesis by promoting outgrowth of cellular projections that are required for a functional biliary network. CDK5 has previously been found to be a major player in the regulation of the formation of neuronal projections during development, and this project will focus on evaluating the role of known pathways that operate through CDK5 in the regulation of cholangiocyte morphogenesis. Understanding the mechanisms that regulate cholangiocyte differentiation and morphology will provide insight into the opposite process observed in cholangiopathies, in which projections retract and differentiation is lost. This information would represent a significant step toward treating a class of diseases that affect thousands of individuals and have poor long-term outcomes. PUBLIC HEALTH RELEVANCE: The biliary network is essential for basic liver function, and cholangiopathies (e.g., primary biliary cirrhosis and primary sclerosing cholangitis) are a major cause of chronic liver disease. This study aims to identify the mechanisms by which the biliary network develops and maintains its differentiated state, which is particularly relevant, as most known cholangiopathies result in a loss of cholangiocyte morphology and differentiation. The goal of this work is in develop a better understanding of cholangiocyte cell biology that will lead to potential therapeutic targets.