Genetic control of mature beta cell function and identity

Project Summary/Abstract Functionally mature beta cells are essential to glucose homeostasis and their loss or dysfunction underlies all types of diabetes mellitus. In recent years, it has become clear that not all beta cells are permanently lost in either type of diabetes. Instead, chronically stressed beta cells lose their functionally mature phenotype and shift to a dysfunctional state in a process called de-differentiation. Preventing or reversing beta cell de- differentiation represents a promising approach to restoring functionally mature beta cell mass in diabetics. We have recently identified five novel genetic regulatory networks that we hypothesize to be important for regulat- ing mature beta cell function and identity. The overarching goal of this proposal is to establish the above five regulatory networks as novel genetic and pharmacological switches for controlling beta cell function and identi- ty. In Aim 1, we will map in detail each of the networks by determining direct and indirect regulated nodes for each regulator. We will further identify the networks' cellular function and find upstream signaling pathways predicted to affect the networks' behavior in both human and mouse beta cells, and their points of perturbation during beta cell de-differentiation. In Aim 2, we will test the causality of the five predicted regulators on beta cell function and identity in vitro in primary mouse and human islets, and in vivo, using genetic mouse models where available. We will further test the effect of genetic intervention points in the networks to lock in place ma- ture beta cell identity under the different diabetogenic stresses.