Objective
The goal of this research is to understand how interferon signaling, the ISR, and palmitoylation interact to drive β cell dysfunction in T1D. We will use three main approaches: (1) study how blocking the ISR affects palmitoylation and immune signaling in β cells; (2) identify which proteins are modified by palmitoylation during interferon exposure; and (3) test whether deleting key palmitoylation enzymes in mice can prevent or delay diabetes. These studies will be conducted using human β cells, human pancreatic islets, and genetically modified mouse models that mimic T1D.
Background Rationale
The incidence of type 1 diabetes (T1D) has been increasing over the past decade, with environmental stressors like early-life viral infections contributing to pancreatic β cell dysfunction through interferon signaling. Interferons are immune proteins that help fight infections, but in T1D, they may cause harm by chronically stimulating the interferon signaling β cells. This overstimulation leads to β cell stress and activates the ISR, which temporarily shuts down protein production to help the cell recover. However, if the ISR remains active for too long, it can lead to cell death. I have shown that blocking parts of the ISR, especially the protein PERK, can delay diabetes in mice. I also found that interferons increase a process called palmitoylation, which modifies proteins like STATs that are involved in downstream interferon signaling. These findings suggest that the interferons, ISR and palmitoylation may work together to worsen β cell stress and promote autoimmunity. My research aims to elucidate how palmitoyl cycling of STAT proteins and the maladaptive ISR drive interferon signaling in T1D development. By characterizing these mechanisms and using genetic models and advanced omics techniques, I aim to inform future therapeutic strategies and R01 submissions.
Description of Project
In type 1 diabetes (T1D), the body’s immune system mistakenly attacks insulin-producing β (beta) cells in the pancreas. These cells are essential for regulating blood sugar. While immune cells are the direct cause of this destruction, recent research suggests that stressed β cells may play a role in attracting immune attacks. One key stress response system in cells is the integrated stress response (ISR), which is activated by signals such as interferons, proteins released during infections or inflammation from immune cells. This project investigates how interferons and the ISR contribute to β cell dysfunction and T1D development. It also explores a process called palmitoylation, where fatty acids are added to proteins, potentially altering how immune signals are processed. By studying these mechanisms in both human cells and mouse models, this research aims to uncover new ways to protect β cells and prevent T1D.
Anticipated Outcome
We expect that blocking the ISR will reduce harmful palmitoylation of key proteins involved in interferon signaling, such as STAT1, and improve β cell survival. In mice, we anticipate that deleting enzymes involved in palmitoyl cycle or using ISR inhibitors will reduce inflammation in the pancreas and delay the onset of diabetes. In human islets, we expect similar protective effects. These outcomes would support the idea that targeting the ISR, interferon and palmitoylation pathways could be a promising strategy to prevent or treat T1D.
Relevance to T1D
While T1D is traditionally viewed as an immune-driven disease, this research highlights the active role of β cells in promoting their own destruction under stress. By focusing on how β cells respond to interferons and how pathways like the ISR and palmitoylation contribute to disease, this project offers a new perspective on T1D pathogenesis. The use of both human and mouse models enhances the relevance of the findings and increases the potential for translating this work into therapies. Ultimately, this research could lead to new treatments that protect β cells and prevent T1D in at-risk individuals.