Citrullinated and deamidated neo-epitopes and their role in murine type 1 diabetes.

Until today, treatment of type 1 diabetes (T1D) includes life-long,

daily insulin administration and patients are still in risk of long-term

complications, which threatens their life expectancy. As evidenced by

the years of intensive research without therapeutic breakthroughs,

we are in need of novel approaches to tackle this disease. T1D

results from the destruction of the pancreatic β-cells by the body’sself

immune system. Interestingly, recent research shed light on the

role of the β-cell in its own destruction. More specific, post

translational modifications, induced by cellular stress, raised

considerable interest as they can induce changes in beta-cell

proteins, resulting in the generation of neo-antigens and eventually in

a break of immune tolerance. Therefore, this project studies the role

of two enzymatically driven post translational modifications,

citrullination and deamidation, in the development of T1D. We will

use the diabetic NOD mice model to identify citrullinated and

deamidated beta-cell proteins and determine their role in disease

progression. Furthermore, we aim to test the impact of targeting

these modifications, both by deletion and inhibition, on the disease

development and we aim to study the mechanisms underlying

disease protection in order to set the stage for the development of

new therapeutic strategies.