Investigating the Role of Twist1 in Diabetes Pathogenesis
Abstract
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 2014 is 9.3% in adult population, and the prevalence tends to increase rapidly, creating enormous economic burden in the United States. Although lifestyle factors (i.e., age, pregnancy, obesity) can increase susceptibility to diabetes, hereditary factors also play critical roles in the incidence of this disease. Diabetes is a complex disease caused by abnormal expression of multiple genes that govern critical aspects of pancreatic development and homeostasis throughout life. 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, Twist1, which encodes for a transcription factor 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 Twist1 in the pancreatic glandular in mice resulted in abnormal pancreatic development and hyperglycemia, reminiscent of diabetes. Supporting this intriguing finding, interrogation of publicly available genomic studies revealed that Twist1 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 Twist1 is consistently associated with pancreatic abnormalities and diabetes. As designed, our proposed experiments will consolidate and expand these initial findings, and ultimately integrate these innovative concepts into our understanding of diabetes. Therefore, completion of this research proposal will provide the proof-of-principle evidence that Twist1 functions as a key regulator of pancreatic development, whose deregulation could contribute to the pathogenesis of diabetes and associated morbidity and mortality. Comprehensive characterization of Twist1 as a novel modifier of pancreatic fate and homeostasis 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
- Jan 31, 2017
- Source ID
- W81XWH1610109
Entities
People
- Azeddine Atfi
Organizations
- United States Army
- University of Mississippi