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产物。它主要通过醛缩酶B（Aldo B）产生，并通过血管内皮细胞中的谷胱甘肽酶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，导致蛋白质糖化和蛋白质功能的改变以及细胞增殖的抑制。调节MG代谢的机制尚不清楚。MicroRNA（miRNAs）是一类非编码的小分子RNA，以序列依赖的方式减少转录后基因的表达。已经报道了果糖和葡萄糖诱导的选择性miRNA的表达变化。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，导致血管内皮细胞中MG代谢的改变和内皮细胞增殖功能的改变。 本研究的目的是：1）检测葡萄糖/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下调是否由特定的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是鉴定的miRNA的选择性靶标;和5）确定葡萄糖/果糖诱导的miRNA失调、MG产生和内皮增殖功能的相关性。该项目将揭示不同miRNA通过选择性靶向AldoB和Gly-I在调节内皮细胞MG代谢中的关键和新颖作用，提供内皮细胞如何响应环境线索改变生长模式的见解，并帮助更好地了解不同发育阶段血管形成的代谢调节。最先进的RNA技术在该计划中的应用也将为培训HQP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.