Hypothesis and specific aims of the project:

We hypothesize that GLP-1 and GIP analogs increase cellular defenses against ER stress in Wolfram syndrome, and prevent or delay β-cell- and retinal neuro-degeneration. Specifically we will examine the impact of WFS1 and WFS2 deficiency on ER stress and β-cell dysfunction and apoptosis, and evaluate whether GLP-1 and GIP analogs improve cellular function and survival using relevant in vitro and in vivo disease models. We will also examine the molecular mechanisms underlying incretin cytoprotection.