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Siglecs as mediators of the pancreatic cellular crosstalk in diabetes (SIADIA)
Start date: Jan 1, 2011, End date: Dec 31, 2015 PROJECT  FINISHED 

The mechanisms of the immune and endocrine cell interaction within the islet and resulting β-cell death arehighly complex and largely unknown. To investigate the cellular crosstalk in the pancreas and how itsdisturbance leads to insufficient insulin production is important to understand the pathology of the disease. Thisis the major goal of this project.Activation of inflammation is not only a trigger for β-cell destruction, but also a major factor for the metabolicsyndrome, including insulin resistance and complications of diabetes.Signalling and activation of immune cells is facilitated by secreted pro-inflammatory stimulators and via cell-cellinteractions. I propose that a group of adhesion and signalling molecules, the Siglecs (sialic acid–bindingimmunoglobulin (Ig)-like lectins) mediate such interactions. They are responsible for immune system activationand have been initially found in cells of hematopoietic origin. I made the groundbreaking observation of celltype specific Siglec expression in the human pancreas: Siglecs were differentially expressed in glucagonproducing α-cells, and in insulin producing β-cells. A diabetic milieu had an inductive effect on Siglecexpression in the α-cells, but lead to decreased β-cell specific Siglecs. This loss of Siglecs in the β-cell could bedetrimental and result in an excessive cytokine release and in turn switches on Siglec responses in neighbouringcells. In my proposed studies I will investigate the role of Siglecs in the cellular network in islets and in thecirculation to probe whether changes in Siglec expression are causative in the development of diabetes.My project is a pioneer and multidisciplinary study combining the current knowledge of glycobiochemistryand β-cell biology in diabetes. The project uses multi-model cell systems of healthy and diseased humanpancreatic tissue, isolated human islets, isolated human β-cells as well as diabetic mouse models, all of thembeing absolutely novel and high-risk to a large extend.
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