Project Abstracts - OPP, New Investigators

Start Date: June 1, 2018
End Date: June 30, 2023

HIRN New Investigator Award Recipient

---

Abstract

Many of the factors that contribute to β-cell death in type 1 diabetes also cause an imbalance in reactive oxygen species (ROS) generation and mitigation. This imbalance can lead to a buildup of ROS, which causes oxidative damage and subsequent apoptosis. β-cells can survive the excessive ROS insult if they are able to implement an antioxidant response. However, it is unclear what distinguishes surviving β-cells from those that undergo apoptosis. Determining the mechanisms responsible for allowing a subset of β-cells to survive under these conditions will allow us to better understand how human β-cells are lost in type 1 diabetes and to therapeutically target those cells more effectively. Based on our observations, and those of others, we hypothesize that reduced oxidative capacity plays a key role in increased β-cell death under conditions that lead to increased ROS. Further, we propose that that interindividual differences in the ability of human islets to mitigate ROS contributes to β-cell failure and the development of diabetes. However, a relative inability to study ROS handling in human islets in vivo has contributed to limited translational progress. Therefore, our objective for this proposal is to develop a platform in vivo for evaluating redox capacity and response to drugs targeting the antioxidant response in human islets. We will utilize novel intravital imaging methodologies to 1) evaluate baseline redox dynamics in islets in vivo from human organ donors, and 2) to test human islet redox capacity with small molecule regulators of the antioxidant response. Overall, these experiments will allow us to define the kinetics of human islet adaptation to ROS accumulation in vivo, and to assess if small molecules can therapeutically rescue deficiencies in this process.