RORalpha and Hepatic Zonal Regulation

肝特异性基因在门脉高压症中央或门脉周围区域的表达受限 成人肝脏，一种被称为区域调节的现象，是肝脏的一个迷人的方面 生物学在过去的10年里，优雅的研究已经揭示了b-连环蛋白的作用， 信号通路控制带状表达。我们最近研究了一本小说 我们开发的小鼠模型系统表明，维甲酸相关孤儿 受体α（RORa）也在控制区域基因表达中起作用。 此外，在其他组织中的研究表明，RORa有助于 干细胞的分化和增殖，但这种特性尚未在 肝脏我们建议使用转基因小鼠和当代高- 通量基因组技术，以探索RORa在功能和干细胞中的作用， 中央周围肝细胞的细胞特性。由于许多肝毒素，包括乙醇， 而药物，如对乙酰氨基酚， 肝细胞，更好地了解控制基因表达的机制， 这种肝细胞亚群的自我更新特性将有助于 减少人类肝细胞损伤的策略。

The restricted expression of specific hepatic genes in pericentral or periportal regions of the adult liver, a phenomenon known as zonal regulation, is a fascinating aspect of liver biology. Elegant studies in the past 10 years have uncovered the role of the b-catenin signaling pathway in controlling zonal expression. Our recent studied using a novel mouse model system developed by us indicates that the retinoic acid-related orphan receptor alpha (RORa) also plays a role in controlling zonal gene expression. Furthermore, studies in other tissues have shown that RORa contributes to the differentiation and proliferation of stem cells, but this property has not been evaluated in the liver. We propose to use genetically modified mice and contemporary high- throughput genomic technologies to explore the role of RORa in the function and stem cell properties of pericentral hepatocytes. Since many hepatotoxins, including ethanol, and pharmaceuticals, such as acetaminophen, specifically damage pericentral hepatocytes, a better understanding of the mechanisms controlling gene expression in and the self-renewing properties of this subpopulation of hepatocytes will help develop strategies to reduce hepatocyte injury in humans.