Type 1 Diabetes: Involvement of Extracellular Matrix in Immune-Mediated Pancreatic Islet Destruction

• Applicant: Dr. Nadine Nagy
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2011 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 213790947

Type 1 diabetes (T1D) affects millions of individuals worldwide and its prevalence and incidence continue to rise annually. Although the triggering mechanism of T1D is still not clear, the entire process must mainly rely on the migration of inflammatory cells from the blood stream into the pancreatic islets via interaction with the ECM that lies between islet capillaries and endocrine cells. It is planned to identify the location, composition and organization of HA and associated macromolecules in human pancreatic islets by microscopic and biochemical analyses. Furthermore, the identification of the cellular source generating this specialized ECM will be discovered. One of the aims of this proposal is to define the characteristic constitutes of non-inflammatory ECM in the pancreatic islets and how this ECM changes during disease progression. In a mouse model of T1D the time course and nature of changes in this specialized ECM relative to the onset of autoimmune islet destruction will be determined in order to define the characteristics of an ECM that promotes inflammation. To investigate the interaction of murine and human T cells with an HA-enriched ECM an in vitro model will be developed. Further the pharmacological inhibition of HA-synthesis as well as the knockdown and overexpression of certain target genes will also be investigated in vitro. In a final step the pharmacological proof of concept is designated in vivo to prove the role of HA during T1D progression. The present study focuses on the role of HA-enriched ECM molecules in creating a permissive environment for autoimmune attacks. The function of ECM in T1D is still understudied. Based on the findings in other inflammatory diseases it is likely, that the HA-enriched ECM mediate the invasion and destruction of islet tissue by T cells, therefore it is crucial to designing effective new therapies to treat T1D.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Thomas N. Wight