Modeling islet inflammation in early-stage type 1 diabetes: T1DstartEd

Objetivo

Understanding the drivers and pathogenic mechanisms of type 1 diabetes (T1D) is a major challenge of biomedicine. Early stages of the disease are characterized by a type I interferon (IFN-I)-driven innate immune response. In addition, genetic studies have identified risk and protective variants in the double-stranded RNA (dsRNA) sensor IFIH1/MDA5. These observations support viral etiology of T1D, with major implications for prevention and therapy. However, a causal virus has not been identified so far despite extensive efforts. We have recently proposed an alternative model, whereby activation of MDA5 and IFN-I occurs via endogenous, rather than viral, transcripts that form dsRNA structures. Specifically, we hypothesized that impaired ADAR-mediated RNA editing of cellular dsRNA can mimic viral infection and trigger islet inflammation. In support of this innovative model, genetic variants that impair endogenous RNA editing are associated with increased risk of T1D. In addition, we found that disruption of RNA editing in mouse and human pancreatic islets induces a robust IFIH1-dependent inflammation and diabetes, and recapitulates key features of early stage T1D.
We propose to study the mechanisms driving unexplained hallmarks of early-stage human T1D that are observed upon RNA editing disruption in beta-cells. We will investigate how metabolic stress and islet architecture impact selective beta-cell destruction; the basis for age-dependent attenuation of IFN-I responses and disease progression; and the immune components responsible for early-stage T1D features. Finally, we will search for RNA editing defects in pancreatic material from T1D patients and assess the pro-inflammatory potential of candidate unedited dsRNAs in human islets.
Our long-term goal is to uncover fundamental principles governing the relationship between RNA editing, IFN responses and inflammation in islets, to understand their impact on T1D, and to identify new approaches for intervention.