Objective
The objective of this grant proposal is to interrogate the role of the ISR in T1D development. There are many proteins that act as gatekeepers for the activation of this pathway and one of the proteins is called PERK. In this study, I will genetically delete PERK in mature β cells of mice that to some extent mimic the autoimmune diabetes in humans. These mice are the non-obese diabetes (NOD) mice. In addition, I will be using chemicals that block this pathway in the cells and will use it in NOD mice as well as a mouse model for virus induced diabetes (as early life viral infections have been associated with triggering diabetes development in genetically predisposed individuals). Moreover, to enhance the translatability of the studies to human context, I will be using human islets treated with these chemical inhibitors under diabetes inducing conditions to see if pretreatment with these drugs reduce the attack on the β cells by the immune cells.
Background Rationale
Viral infection, nutrient depletion, and generalized inflammation are among the environmental insults that pose a stressful burden on β cells. Under these conditions, cellular proteins are not properly folded and therefore cannot function appropriately. To cope with these stresses, the ISR pathway is activated to enable blockade of synthesis of new proteins in order to conserve cellular energy and maintain balance. However, problem arises when this stress response system continues to block the synthesis of new proteins as this leads to a loss of equilibrium and the cells die due to the lack of essential proteins to function properly. Therefore, elucidating the role of ISR in the β cells in T1D will pave way for potential therapeutics.
Description of Project
The beta cells (β cells) in the pancreas sense prevailing blood glucose levels and, in response, release insulin. In T1D, β cells are destroyed or rendered dysfunctional by the immune system. The trigger that provokes the immune system to destroy the β cells is unknown. However, recent evidence points toward the possibility that signals are first sent out by β cells under stressful conditions such as viral infections or generalized inflammation that eventually attracts immune cells. There are several stress reduction systems that are adapted by β cells under conditions of stress. However, when these adaptive responses become prolonged, they turn maladaptive and result in cell death. A key stress response known as the integrated stress response (ISR) is activated under a variety of stressful stimuli. However, the role of the ISR in the context of T1D is unknown. Therefore, I propose to study the ISR in the βcells to determine its role in initiating and/or propagating type 1 diabetes.
Anticipated Outcome
Our previous research points towards the increase of the ISR in the pre-diabetic phase of diabetes development in mice. Additionally, our preliminary pre-clinical data using PERK inhibitor in mice revealed reduction in inflammation in and around the pancreatic islets as well as a delay in progression to diabetes. Therefore, we believe that depletion of PERK in the β cells will yield similar outcomes. Additionally, we anticipate that systemic blockade of the ISR using chemical inhibitors will reduce islet inflammation as well as reduce diabetes incidence.
Relevance to T1D
Our previous research points towards the increase of the ISR in the pre-diabetic phase of diabetes development in mice. Additionally, our preliminary pre-clinical data using PERK inhibitor in mice revealed reduction in inflammation in and around the pancreatic islets as well as a delay in progression to diabetes. Therefore, we believe that depletion of PERK in the β cells will yield similar outcomes. Additionally, we anticipate that systemic blockade of the ISR using chemical inhibitors will reduce islet inflammation as well as reduce diabetes incidence.