Functionalizing a T1D/T2D-associated locus within an intron of GLIS3.
NIH
UNIVERSITY OF WISCONSIN-MADISON
PROJECT SUMMARY  Diabetes mellitus has been characterized since antiquity, with the first documentation of this group of disorders dating back to 1500 BC1. While many advances have been made in the field in terms of treatment, there remains no cure for diabetes. This has become increasingly problematic for both the individuals and the entire healthcare system as rates of diabetes continue to rise. It is estimated that healthcare for individuals with diabetes costs over $200 billion per year in the United States alone2. Diminishing these costs and improving treatment options for patients are just a couple of the many reasons why diabetes-related research is so critical.  I will use a genetic approach to more fully understand the initiation and progression of diabetes. In this application, I highlight a method that integrates human and mouse datasets to examine the role of intragenic and intronic regions of the genome in diabetes susceptibility. One such locus of interest resides in the first intron of the GLIS3 gene and has highly significant SNPs associated with both type 1 diabetes (T1D) and type 2 diabetes (T2D). To study this Glis3T1D/T2D locus, we determined the syntenic region in mouse and deleted 1729bp to create a novel mouse model (Glis31729 mouse). I found that these mice exhibit hyperglycemia, despite increased insulin secretion and glucose-evoked Ca2+ oscillations. My overall objective for this proposal is to functionalize this locus in an effort to elucidate its role in driving diabetes. My central hypothesis for the function of this locus is that it acts as an enhancer for Glis3 in islets, and that T1D/T2D-related SNPs within the locus alter its activity. I will test this hypothesis, and thus accomplish the goals of this proposal, by pursuing the following aims: 1) evaluate the enhancer activity of the Glis3T1D/T2D locus, 2) identify the influence of T1D/T2D-associated SNPs on transcription factor binding at the Glis3T1D/T2D locus, and 3) evaluate differentially expressed (DE) genes in the Glis3 1729 mice to reveal the role of the Glis3T1D/T2D locus on altering T1D and T2D risk. With the completion of these aims, I anticipate a more complete understanding of this non-coding locus, including how it regulates gene expression and affects both type 1 and type 2 diabetes susceptibility. Additionally, I believe this proposal will provide the necessary training for me to progress as an islet biologist and prepare me for a tenure-track position at a research institution. PROJECT NARRATIVE  Diabetes is a complex chronic disease that is largely driven by genetic factors. This proposal aims to determine the function of a T1D and T2D – associated locus located in an intronic region of GLIS3. Further characterizing this locus will help elucidate its role in altering diabetes susceptibility and may provide a mechanism for a novel shared pathophysiology at the genetic level for T1D and T2D.
Training, Individual