University of California, San Francisco (UCSF)

Endoplasmic Reticulum Stress and Type 2 Diabetes

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The research supported through our Hillblom Start-Up award aims to understand how endoplasmic reticulum (ER) stress leads to pancreatic beta cell death in the development of diabetes. Using funding from the Hillblom Foundation, we have created chemical-genetic systems for manipulating a cellular pathway called the unfolded protein response (UPR) to adjust the life-death decision faced by cells when they encounter ER stress. These tools are based on our observation that providing a cell-permeable inhibitor to an inhibitor-sensitized Ire1alpha kinase can confer significant cytoprotection to such engineered cells under ER stress. Our tools are portable, and will be imported into beta cells of living mice using transgenic technology to ask whether diabetes can be forestalled under conditions when unfolded proteins build up in beta cells. If successful, the work has the potential to identify and validate a new target for pharmaceutical intervention in diabetes mellitus. We anticipate that our strategy will be widely applicable to the study of other protein misfolding diseases, such as neurodegeneration.