乙型肝炎病毒反式调节蛋白对胰岛β细胞功能的作用及机制的研究

Hepatitis B complicated by diabetes is a common complication in patients with Hepatitis B virus (HBV) infection. The mechanism underlying the complication of hepatitis B remains unclear. Studies suggested that HBV may impair the function of pancreatic islet β cells owing to its pantropic infection. Analysis of gene-chip data indicated that HBV can enhance the gene expression of lysophosphatidic acid (LPA)-generating enzyme autotaxin (ATX). Our previous research revealed that LPA involves in the regulation of insulin secretion. And LPA was newly reported to inhibit insulin secretion. These results of studies and analysis suggest that HBV may inhibit insulin secretion via up-regulating ATX gene expression, enhance ATX/LPA signaling and thereby accelerate the pathogenesis of hepatitis B complicated by diabetes. In this project, we intend to investigate the effects of HBV trans-regulatory proteins on ATX/LPA signaling and their impact on insulin secretion by using the expression vectors of HBV X protein (HBx) and pre-S2 protein (pre-S2) which are the major HBV trans regulators, LPA receptor antagonist Ki16425 and HBV transgenic mice,elucidate the molecular mechanism, clarify the roles of HBx and pre-S2 in the pathogenesis of hepatitis B complicated by diabetes and thus provide experimental basis for further study of the molecular mechanism underlying the diabetes complication of hepatitis B.

乙型肝炎并发糖尿病是乙型肝炎患者的常见并发症，其发病机制尚不明确。有研究提示，乙型肝炎病毒（HBV）因其泛嗜性感染可能损害胰岛β细胞的分泌功能。基因芯片分析发现HBV可增强溶血磷脂酸（LPA）生成酶Autotaxin (ATX)的基因表达。我们前期的研究表明LPA参与胰岛素分泌的调节，而新近的研究报道指出LPA可抑制胰岛素分泌。这些研究和分析结果提示，HBV可能通过上调ATX的表达，从而增强ATX/LPA信号转导而抑制胰岛素分泌，促进乙型肝炎并发糖尿病。本项目拟应用HBV的主要反式调节蛋白HBx和pre-S2的表达载体、ATX/LPA信号转导拮抗剂Ki16425和HBV转基因小鼠研究HBx和pre-S2对ATX/LPA信号转导的作用及其对胰岛素分泌的影响，阐明其分子机制，明确HBx和pre-S2在乙型肝炎并发糖尿病发病中的作用，为进一步研究乙型肝炎并发糖尿病的发病机制提供实验依据。

乙型肝炎并发糖尿病是乙型肝炎患者的常见并发症，其发病机制尚不明确。有研究提示，乙型肝炎病毒（HBV）因其泛嗜性感染可能损害胰岛β细胞的分泌功能。基因芯片分析发现HBV可增强溶血磷脂酸（LPA）生成酶Autotaxin (ATX)的基因表达。我们前期的研究表明LPA参与胰岛素分泌的调节，而新近的研究报道指出LPA可抑制胰岛素分泌。这些研究和分析结果提示，HBV可能通过上调ATX的表达，从而增强ATX/LPA信号转导而抑制胰岛素分泌，促进乙型肝炎并发糖尿病。本项目拟应用HBV的主要反式调节蛋白HBx和pre-S2的表达载体、ATX/LPA信号转导拮抗剂Ki16425和HBV转基因小鼠研究HBx和pre-S2对ATX/LPA信号转导的作用及其对胰岛素分泌的影响，阐明其分子机制，明确HBx和pre-S2在乙型肝炎并发糖尿病发病中的作用，为进一步研究乙型肝炎并发糖尿病的发病机制提供实验依据。