Grant: Discovery Grants Program - Individual

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.