Driving Next Generation UPR Inhibitory Kinase Inhibitors for T1D
Contact PI: Feroz Papa, MD, PhD, University of California, San Francisco (U01 DK143500)
Dustin Maly, Investigator, University of Washington
Bradley Bickes, PhD, University of California, San Francisco
Start Date: August 1, 2025
Abstract
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 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 next-generation “PAIR” molecules for potency and selectivity, conduct proof-of-concept studies using human islets (ex vivo and in transplanted mice), and perform key enabling steps needed to advance these candidates further into the clinic for treating human patients with T1D.
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