Genetics and autoantibody heterogeneity of autoimmune diabetes: implications for precision medicine

Proponente Raffaella Buzzetti - Professore Ordinario
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca

The identification of new pathways to prevent ß-cell failure is crucial to finding a cure for autoimmune diabetes (AD). The study of subjects naturally protected from ß-cell deficiency despite the presence of islet autoimmunity may reveal new protective mechanisms in AD. Subjects with Latent Autoimmune Diabetes of the Adults (LADA) are characterized by an adult onset and by a slow progression of ß-cell destruction, compared to type 1 diabetes (T1D).The study of AD heterogeneity in terms of genetic and humoral differences between T1D and LADA may therefore highlight new potential therapeutic pathways.
In this research project we will study the heterogeneity of genetic polymorphisms of risk (in human leukocyte antigen -HLA, Cytotoxic T-Lymphocyte Antigen 4 -CTLA4, Protein tyrosine phosphatase non-receptor type 22 -PTPN22, insulin genes) and protection (calcyphosine-like-Interleukin-7 receptor, Interlunkin-10 and Solute Carrier Family 30 Zinc Transporter Member 6 genes) for autoimmune disorders and the differences between T1D and LADA. Moreover, we will evaluate the differential role of autoantibodies to Interferon alfa (AbIFNa) in T1D and LADA patients and the involvement of oxidative post-translational modifications (oxPTM) of three main ß-cell antigens (insulin, GAD, IA-2). Differences in microvascular complication will be evaluated. To these aims we will collect data from validated dataset and biobank of more than 800 patients with AD already available to this investigator. Further adult and pediatric patients with T1D and LADA will be enrolled.
We expect to show that polymorphisms associated with protection from autoimmune disorders and AbIFNa are differentially associated with less aggressive forms of AD. New pathophysiological pathways leading to AD will be explored investigating the role of oxPTM in patients with LADA.
This project will provide new insights into the mechanisms of ß-cell failure and/or protection, revealing potential targets for AD treatment.

LS4_3, LS4_5

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