硫还原蛋白结合蛋白Txnip的基因表达调控研究

Thioredoxin Interacting Protein (Txnip) is an important regulator of cellular glucose and fatty acid metabolism and of cellular redox state. Exemplified in human and murine studies, Txnip is implicated in diseases such as diabetes and cancer. In humans, the expression of the Txnip gene is frequently up-regulated in (pre-)diabetic subjects and down-regulated in a variety of cancers; mice lacking Txnip exhibit fasting hypoglycemia and hyperlipidemia and dramatically increased incidence in hepatocellular carcinoma. Txnip functions by inhibiting peripheral glucose uptake and utilization and promoting hepatic gluconeogenesis as well as by inhibiting cell proliferation and inactivating thioredoxin, leading to increased oxidative stress. Altering Txnip expression has been suggested as a promising therapeutic approach in both diabetes and cancer. At the transcriptional level, Txnip expression is dependent upon glucose and highly regulated by other physiological and pharmacological stimuli; we have recently made a number of important discoveries suggesting ways of manipulating Txnip expression. Thus, we showed that Txnip mRNA expression is negatively regulated by glycolytic flux and stimulated by adenosine-containing compounds. We have also found that the widely used antidiabetic drug metformin markedly inhibits Txnip expression. We propose that this effect is important in its mechanism of action. The goal of the proposed project is hence to characterize molecular details regarding how glycolysis, metformin and adenosine-containing compounds regulate Txnip expression. To this end, we are planning to use a variety of complementary approaches comprising in vitro and cell signaling studies to identify glycolytic intermediate(s) responsible for glucose-induced Txnip expression and to delineate the underlying mechanism. We are also proposing studies to elucidate how metformin and adenosine-containing compounds regulate Txnip expression on a molecular level, with a goal of identifying novel therapeutic targets towards inhibiting or up-regulating Txnip expression in diabetes and cancer, respectively.

硫还原蛋白结合蛋白（Thioredoxin interacting protein; Txnip）是一个多功能蛋白，其基因异常与众多疾病相关。例如，Txnip基因 在II类糖尿病者外围组织表达过高,而与其作为抑癌基因相对应的是在很多肿瘤细胞中低或不表达；在小鼠模型中，Txnip 基因的失活导致低血糖症，高血脂症和极高的肝癌罹患率。以上这些表现与Txnip蛋白能够抑制外围组织葡萄糖吸收，增加肝脏葡萄糖异生，扼制细胞分裂以及弱化硫还原蛋白导致氧化胁迫（oxidative stress）有关。我们发现Txnip 基因的表达不仅严格地依赖葡萄糖，并且受其他代谢因子诸如含腺苷分子，氧化磷酸化抑制物以及抗糖尿病药二甲基胍（metformin）的调控；拟进一步揭示Txnip 基因表达受这些代谢因子调控的详尽分子机制进而探究Txnip的功能，旨在为干预糖代谢异常相关疾病（包括肿瘤）提供理论指导。