Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by hyperglycemia due to progressive immune-mediated destruction of pancreatic beta cells. Recent work from our laboratories has shown that hyperactivation of the unfolded protein response (UPR) to ER stress in the immune-targeted beta cells may be a critical early event in the development of T1D. We have developed novel pharmacological reagents called `PAIR's that allow us to manipulate components of the UPR. Importantly, first generation versions of small molecules?called KIRAs? delivered to NOD mice can efficaciously prevent and even reverse diabetes in this T1D model. Thus, in this collaborative grant we will capitalize on the complementary expertise of the investigators to optimize these PAIR lead molecules for potency and selectivity, conduct proof of concept studies using human islets, and perform key enabling steps needed to advance these candidates further into the clinic for treating human patients with T1D.
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by hyperglycemia due to progressive immune-mediated destruction of pancreatic ?-cells. The high protein secretion burdens of ?-cells predisposes them to significantly higher levels of endoplasmic reticulum (ER) stress compared to non- secretory cells. Recent work from our laboratories has shown the activation of stress response pathways such as the unfolded protein response?UPR?may be an initial causal event in the development of T1D. In this collaborative MPI U01 grant to HIRN we capitalize on the complementary expertise of the investigators and pharmacologically target the UPR with novel chemical matter?called PAIRs?as new ?-cell sparing therapeutic approaches for T1D.
