Type 1 diabetes (T1D) is characterized by the destruction of the insulin-producing islet β-cells by the immune system, a feature that leads to elevated blood sugars. The lion’s share of research over the past several decades has focused on immune cells as the culprits for the disease progression. However, an emerging perspective suggests that β-cells exhibit features that alarm the immune cells, thereby initiating a cascade of events that lead to their demise. In this project, we will be studying a molecular process in β-cells that may provoke the immune cells.
Polyamines are a class of molecules produced by a cell and are responsible for the ability of a cell to stabilize DNA and proteins. Some of the proteins and DNA molecules affected by polyamines may contribute to provoking immune cells. Therefore, we feel that limiting the level of polyamines can have beneficial effects, including the suppression of immune responses. In this respect, it has been shown by other investigators that levels of certain polyamines are elevated in individuals with diabetes. This finding may suggest that these polyamines could contribute to the development of the disease. The initial production of polyamines is governed by a protein known as ornithine decarboxylase (ODC). In animal models of T1D, it has been shown that the levels of ODC are enhanced. These findings suggest the possibility that blocking the function of ODC could be a strategy to prevent T1D. Our lab has previously discovered that mice at risk for T1D demonstrate a delay in disease onset when administered a blocker of ODC known as difluoromethylornithine, or DFMO. These exciting findings necessitate a closer look at polyamines and how they might function in T1D.
In this project, we will investigate the role of polyamines by using genetically-altered mouse models as well as human islets to decipher the interplay between polyamines, β-cells, and the immune system. The specific goals of this study are:
- Determine the contribution of polyamine synthesis to the incidence of type 1 diabetes in mice.
- Determine the contribution of islet polyamine synthesis on immune cell activation
With the multi-disciplinary expertise of our lab in islet biology and immunology and by employing state-of-art technologies, this study will fill the critical gaps in the knowledge regarding the inciting events leading to T1D and open doors to potential therapeutics to prevent and/or delay the development of T1D.