Investigating the Role of TGIF in Beta Cell Function and Diabetes
Abstract
Topic Area: Diabetes. Diabetes has become epidemic in our modern society, likely due to calorie-rich diets overwhelming our adaptive metabolic systems. Diabetes patients usually develop a variety of debilitating complications, prominent among them neuropathy, nephropathy, and cardiovascular diseases, which are the main causes of mortality in diabetic patients. A global prevalence rate of diabetes in the United States is 9.3% (or 29.1 million), and the prevalence tends to increase rapidly, creating enormous economic burden. Although lifestyle factors (i.e., age, pregnancy, obesity) can increase susceptibility to diabetes, hereditary factors also play critical roles. Diabetes is a complex disease caused by abnormal expression of multiple genes that govern critical aspects of pancreatic function and homeostasis. Several potential genes associated with diabetes have been identified by integrative genomic approaches, yet their contribution to the pathogenesis of diabetes remains to be established. In this proposal, we intend to focus our efforts on one of these candidate diabetes genes, TGIF, which encodes for a transcription repressor that is known to govern fundamental biological processes crucial for proper body development and maintenance of organ homeostasis throughout life. Our serendipitous finding unveiled that enforced expression of TGIF in the pancreatic glandular in mice resulted in chronic hyperglycemia, the main cause of diabetes. Supporting this intriguing finding, interrogation of publicly available genomic studies revealed that TGIF is highly associated with diabetes in large cohorts of human diabetic patients. To the best of our knowledge, this is the first study to show that TGIF is consistently associated with diabetes. As designed, our proposed experiments will consolidate and expand these initial findings and ultimately integrate these innovative concepts into our understanding of diabetes. As such, completion of this research proposal will provide the proof-of-principle that TGIF functions as a key regulator of pancreatic function, whose deregulation could contribute to the pathogenesis of diabetes and associated morbidity and mortality. Comprehensive characterization of TGIF as a novel diabetes gene modifier will open up new angles to the diabetes field, both in terms of understanding the mechanisms underlying diabetes development and evolution and in terms of drug discovery to curb this life-threatening disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710116
Entities
People
- Azeddine Atfi
Organizations
- United States Army
- University of Mississippi