Regulators that Mediate the Cellular Response to Chronic Hyperglycemia
Dissecting the interaction between genetic and environmental factors can be facilitated through the genetic analysis of gene expression. In order to cope with the stress of chronic hyperglycemia cells rely in part on changes in gene expression to coordinate a complex cellular response. The extent to which certain genes are up or down-regulated influences how well the cells handle the diabetic micro-environment. Individuals differ in their response to hyperglycemia. Heritability studies prove that at the genomic level individuals with diabetic complications are different from those who do not develop diabetic complications. Twin and familial aggregation studies clearly demonstrate that there is an individual genetic susceptibility for diabetic complications. As there is a large genetic predisposition for the development of diabetic complications, inter-individual differences in genomic DNA variation should be revealed by corresponding differences in the genomic response to the same environmental stimulus. In other words underlying DNA variation between individuals will be reflected by differences in the provoked gene expression response to hyperglycemia. Hence, we hypothesize that the genomic response to hyperglycemia varies among individuals. The purpose of this pilot study is to test this hypothesis by evaluating changes in the transcriptomic profiles of DCCT/EDIC subject cell lines to chronic hyperglycemia. The value of this proposal is that it will lay the foundation for future studies that can then map and genetically identify the regulators that control the cellular response to hyperglycemia. The activity of these regulators can then be assessed in individuals with diabetic complications. In summary, differential gene expression response to hyperglycemia can be leveraged to determine the regulators that control the cellular response to hyperglycemia. The regulators can be found by mapping the DNA loci (eQTLs) that are responsible for the gene expression variation. Thus, these hyperglycemia-response regulators will suggest novel targets for interventions that better treat and hopefully one day prevent these debilitating diseases.

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