微小RNA-222与妊娠诱导的肝脏增大的关系及其意义

从生理功能适应性改变的过程中去探究疾病的机制和治疗，是病理生理学研究的新思路之一。促进肝脏再生对于肝病的治疗具有重要意义。已知妊娠可诱导肝脏增大，是一个独特的促进肝再生的生理性刺激，但其对肝细胞增生和肝重构的机制、特别是微小RNA在其中的作用尚不明了；从妊娠诱导的角度探索肝脏再生，也是尚未被关注的研究模型。我们前期的研究提示，微小RNA-222在妊娠诱导的小鼠肝脏生理性增大中显著下调。本课题拟在此基础之上，运用转基因动物和脏器特异性基因敲除动物，结合分子、细胞水平和活体水平的实验，探明微小RNA-222与肝脏再生的关系，揭示微小RNA-222下调介导肝脏生理性增大时肝细胞增大和增殖的分子基础。以此为依据，进一步探索抑制微小RNA-222表达可否用于防治急性肝功能衰竭。通过本项目的研究，将鉴定出一个妊娠诱导的肝脏生理性增大的关键微小RNA，并探索一种新的治疗急性肝衰竭的方法。

Pregnancy-induced hepatic growth is characterized by hepatocyte proliferation and hypertrophy. Pregnancy is a unique physiological stimulus to liver regeneration and promoting liver regeneration is extremely valuable for the treatment of liver diseases. Pregnancy represents a relatively unexplored model system to investigate the regulation of hepatocyte proliferation and liver remodeling. The role of microRNAs (miRNAs, miRs) in pregnancy-induced hepatic growth is unclear. Our preliminary data based on microRNA arrays and quantitative reverse transcriptase-polymerase chain reactions has indicated that miR-222 was elevated in pregnancy-induced hepatic growth. Based on these results, firstly, we will claify the role of miR-222 in pregnancy-induced hepatic growth through loss-of-function and gain-of-function experiments in vitro and in vivo as well. Secondly, we will identify the target genes of miR-222 in promoting hepatocyte proliferation and hypertrophy through gene arrays, bioinformatic analysis, luciferase reporter assays and Western Blot. Finally, we will investigate whether suppressing the expression of miR-222 in liver is protective for acute liver failure in vivo. Our project will identify a critical miRNA responsible for pregnancy-induced hepatic growth and also provide a potential therapeutic approach for acute liver failure.