MicroRNA-regulated methylglyoxal metabolism in vascular endothelial cells

甲基乙二醛（MG）是哺乳动物细胞中葡萄糖和果糖的代谢物。它主要在血管内皮细胞中通过醛缩酶B （AldoB）产生，并通过乙二醛酶I （Gly-I）解毒。葡萄糖和果糖通过不同的途径在血管内皮细胞中产生MG，导致蛋白质糖基化，改变蛋白质功能，抑制细胞增殖。调控MG代谢的机制尚不清楚。MicroRNAs （miRNAs）是一种小的非编码rna，以序列依赖的方式减少转录后基因的表达。果糖和葡萄糖诱导的选择性mirna表达变化已被报道。我们假设葡萄糖和果糖选择性地调节特定mirna的表达，从而差异调节AldoB和Gly-I的表达，导致血管内皮细胞MG代谢改变和内皮细胞增殖功能改变。该项目的目的是：1)检查葡萄糖/果糖对血管内皮细胞中AldoB和Gly-I的影响；2)检测葡萄糖/果糖诱导的AldoB上调和Gly-I下调是否由特异性mirna介导；3)探索葡萄糖/果糖诱导的靶向AldoB或Gly-I的miRNA失调的途径；4)确认AldoB和Gly-I是所鉴定的mirna的选择性靶点；5)确定葡萄糖/果糖诱导的miRNA失调、MG生成和内皮细胞增殖功能的相关性。该项目将通过选择性靶向AldoB和Gly-I，揭示不同mirna在调节内皮细胞MG代谢中的关键和新作用，为内皮细胞如何响应环境线索改变生长模式提供见解，并有助于更好地理解不同发育阶段血管形成的代谢调节。最先进的RNA技术在该项目中的应用也将为hqp的培训提供一个很好的机会。

Methylglyoxal (MG) is a metabolite of glucose and fructose in mammalian cells. It is mainly generated via the enzyme aldolase B (AldoB) and detoxified via glyoxalase I (Gly-I) in vascular endothelial cells. Glucose and fructose, via different pathways, produce MG in vascular endothelial cells, leading to protein glycation and changes in protein functions as well as the inhibition of cell proliferation. The mechanisms that regulate MG metabolism have been unclear. MicroRNAs (miRNAs) are small non-coding RNAs that reduce post-transcriptional gene expression in a sequence-dependent manner. Fructose- and glucose-induced expressional changes of selective miRNAs have been reported. We hypothesize that glucose and fructose selectively regulate the expression of specific miRNAs so that the expressions of AldoB and Gly-I are differentially regulated, leading to altered MG metabolism in vascular endothelial cells and altered endothelial proliferative functions. The objectives of this program are to 1) examine the effects of glucose/fructose on AldoB and Gly-I in vascular endothelial cells; 2) test whether glucose/fructose-induced upregulation of AldoB and downregulation of Gly-I are mediated by specific miRNAs; 3) explore the pathways for glucose/fructose-induced dysregulation of miRNA that target AldoB or Gly-I; 4) confirm AldoB and Gly-I being the selective targets of the identified miRNAs; and 5) determine the correlation of glucose/fructose-induced miRNA dysregulation, MG production, and endothelial proliferative functions. This program will unveil critical and novel roles of different miRNAs in regulating MG metabolism in endothelial cells by selectively targeting AldoB and Gly-I, provide insight on how endothelial cells respond to environmental cues with altered growth patterns, and help gain a better understanding on the metabolic regulation of vascular formation at different developmental stages. The application of state-of-the-art RNA technologies in the program will also offer a great opportunity for training HQPs.