Prolonged hyperglycemia leads to cardiovascular disorders (CVD), which in turn is the most prevalent cause of mortality in diabetic patients. In type 2 diabetes (T2D), whereas insulin resistance can be viewed as a triggering event, loss of functional beta cell mass is required for the full development of this devastating disease. Therefore, preventing a loss of functional beta cell mass is essential in treating T2D. Functional beta cell mass is controlled by bidirectional changes in the size, number, and functional capacity of beta cells. Understanding the molecular mechanisms of beta cell death in presence of prosurvival signals in T2D setting forms the basis of this project. EGFR signaling plays a critical role in controlling beta cell proliferation, survival, and repair mechanisms: all features relevant to maintaining beta cell mass, and is dampened by glucolipotoxicity (GLT). Mig6, a negative regulator of EGFR signaling, is the primary feedback controller of EGFR signaling in beta cells. Our preliminary studies indicated that Mig6 interacted dynamically with numb and beta-catenin in a context dependent manner; Mig6: numb interactions were observed in low glucose conditions whereas Mig:beta-catenin interactions were observed only in GLT. Numb and beta-catenin aberrantly accumulated in the nucleus in GLT, which potentially stabilize p53 and trigger cell death. As numb and beta-catenin are part of Notch and Wnt signaling, both of these pathways could be deregulated in GLT. This proposal aims to test the hypothesis that Mig6 is a central regulator of EGFR, Notch, and Wnt signaling pathways to determine beta cell fate in a context-dependent manner in T2D.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||07/01/2018 → 06/30/2020|