Pancreatic beta cell death marks a critical turning point in the development of diabetes. In type 1 diabetes, a combination of cytokines trigger beta cell inflammation ultimately leading to beta cell apoptosis. We have focused our research efforts on understanding signaling mechanisms that modulate the progression of beta cell inflammation and found that the pseudokinase TRB3 plays a key role in augmenting mechanisms that lead to cell death. We find that TRB3 is instrumental in compromising mitochondrial integrity while others have reported a role for TRB3 in ER stress. Both mechanisms likely contribute to susceptibility of beta cell to proapoptotic stimuli. TRB3 has been characterized as a negative regulator of AKT, a prosurvival kinase that is indispensible for the survival and normal funtioning of the beta cell. We provide preliminary data to suggest that beyond AKT, TRB3 also modulates the function of several inflammatory proteins in the beta cell. In this grant we will further defin examine molecular mechanisms that enable TRB3-mediated fine tuning of beta cell survival and death. We propose the following specific aims: 1) Elucidate the mechanism by which TRB3 modulates inflammatory signaling 2) Explore the role of TRB3 in ER-mitochondrial crosstalk and 3) Examine how post-translational modifications alter the biological role of TRB3 in beta cells.
Diabetes is one of the fastest rising diseases in the USA and indeed worldwide. The disease imposes great human and financial costs, which are only likely to increase in the forseeable future. This project addresses the mechanisms by which the pseudokinase TRB3, an intrinsically inactive factor, modulates cellular signaling events to tip the balance in favor of inflammation and loss of insulin secreting beta cells.
