ARRA: Histone Acetylation and Insulin Gene Expression

Diabetes is a serious disease affecting nearly 150 million people world wide. One of the major causes of diabetes is the inability of pancreatic 13-cells to produce and secrete sufficient amounts of insulin required for glucose disposal, which results in hyperglycemia. Chronic hyperglycemia leads to further deterioration of 13- cell function causing glucose toxicity. MafA, an insulin gene transcription factor specific to pancreatic beta- cells, has a critical role in regulating insulin gene transcription, insulin secretion, beta-cell maturation and survival. Although it is known that MafA expression is up-regulated by high concentrations of glucose and down-regulated during diabetes, the exact mechanisms and signaling events controlling MafA levels in pancreatic beta cells remain to be established. This requested administrative supplement for students and science educators is related to Specific Aim #3 of our parent NIH 5R01 0K067581-05 grant, where we proposed to study the molecular mechanisms leading to high-glucose induction of the beta-cell transcription factor MafA. We have recently discovered that MafA levels are regulated by glucose via increased flux through the hexosamine biosynthesis pathway and 0-linked GIcNAc modificaiton. We propose that 0-linked GIcNAc modification of an unknown transcription factor stimulats MafA expression by high glucose. The proposed research is part of our ongoing studies to understand the regulation of pancreatic beta-cell function by glucose as covered by our parent grant. We will use the funds from this administrative supplement to support summer research for ten weeks for two minority undergraduate students and for one science educator. The two undergraduate students will be recruited from a pool of minority students who apply to our departmental NSF-REU Summer Program in Biochemical Sciences and from the University of Kentucky "Bucks for Brains" Summer Research Program. We had already several talented minority students through these two programs over the past several years, who successfully completed research projects in our laboratory. The sience educator will be recruited from the local Bluegrass Community & Technical College.