Species-Specific Regulation of Autoantigen Processing: A Humanized Mouse Model of Cathepsin D in Type 1 Diabetes

About This Grant

ABSTRACT Type 1 diabetes is an autoimmune disease where the immune system mistakenly attacks and destroys insulin-producing beta cells in the pancreas. Our research has discovered unique hybrid molecules, called Hybrid Insulin Peptides (HIPs), that form in beta cells when fragments of insulin fuse with other protein fragments. Various HIPs contributing to disease in humans and mice are generated by an enzyme called Cathepsin D and serve as key targets for the immune system’s attack on beta cells. Interestingly, while HIPs are consistently detectable in laboratory mice used to study diabetes, they are harder to detect in human tissue samples even when analyzing larger amounts. We discovered this difference stems from how HIPs are made: the human version of Cathepsin D requires more acidic conditions to function compared to the mouse version. This could explain why human and mouse diabetes look different under the microscope - mice show widespread inflammation throughout the pancreas, while humans show more localized damage. To better understand how HIPs form in human disease, we propose to create a new mouse model where we replace the mouse version of Cathepsin D with the human version. We expect these “humanized” mice will form HIPs less readily, similar to humans. This model will help us understand how environmental factors influence HIP formation and disease development, potentially identifying new ways to prevent or treat type 1 diabetes. This research could reveal important insights into why type 1 diabetes develops and how environmental factors might influence disease progression through their effects on HIP formation, potentially leading to more effective prevention strategies.