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 that allow us to manipulate components of the UPR. Importantly, these small molecules 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 lead molecules for oral delivery, conduct proof of concept studies, and perform key enabling steps needed to advance these candidates 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 beta cells. The high protein secretion burden of beta 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 grant we capitalize on the complementary expertise of the investigators and pharmacologically target the UPR with novel chemical matter called KIRAs as new therapeutic approaches for T1D.
| Morita, Shuhei; Villalta, S Armando; Feldman, Hannah C et al. (2017) Targeting ABL-IRE1? Signaling Spares ER-Stressed Pancreatic ? Cells to Reverse Autoimmune Diabetes. Cell Metab 25:883-897.e8 |
| Feldman, Hannah C; Tong, Michael; Wang, Likun et al. (2016) Structural and Functional Analysis of the Allosteric Inhibition of IRE1? with ATP-Competitive Ligands. ACS Chem Biol 11:2195-205 |
| Ghosh, Rajarshi; Wang, Likun; Wang, Eric S et al. (2014) Allosteric inhibition of the IRE1? RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158:534-48 |
| Maly, Dustin J; Papa, Feroz R (2014) Druggable sensors of the unfolded protein response. Nat Chem Biol 10:892-901 |
