Unlocking and blocking the molecular mechanisms of redox regulation in β-cells

The islets of Langerhans are the endocrine component of the pancreas and their dysfunction, in particular the β-cells, results diabetes. Currently there is no cure for diabetes. Thus, new strategies to preserve β-cells are needed.

Protecting β-cells against high levels of intracellular reactive oxygen species (ROS) represent and novel approach to tackle diabetes and preserve β-cell function. Central contributors to increased intracellular ROS levels in β-cells are the NOX enzymes.

ROS (e.g. hydrogen peroxide) are produced by NOX enzymes at the plasma membrane upon increased glucose levels, and transported into the cell by a member of the aquaporin family, AQP3.

However, the details of the molecular mechanisms regulating this cellular circuit are not clear.In this project proposal we aim to decipher the molecular mechanisms of NOX associated ROS production in β-cells, and the intracellular signaling consequences, like insulin secretion.

In addition, we aim to develop inhibitors targeting membrane proteins important for ROS regulation in β-cells, by making use of the recent developments in single particle cryo-EM and combine that with functional studies in cells and rational design of inhibitors.

Thus, when this project is executed, it will not only result in understanding of the regulatory mechanisms behind ROS induced insulin secretion in pancreatic β-cells but also pave the way for novel therapeutic options towards treating diabetes.