detection of molecular paths associated with insulitis and type 1 diabetes in non-obese diabetic mouse检测的分子路径与非肥胖糖尿病小鼠胰岛炎和1型糖尿病.pdfVIP

Detection of Molecular Paths Associated with Insulitis and Type 1 Diabetes in Non-Obese Diabetic Mouse 1 1 2 ˇ ˇ 1 Erno Lindfors , Peddinti V. Gopalacharyulu , Eran Halperin , Matej Oresic * 1VTT Technical Research Centre of Finland, Espoo, Finland, 2 International Computer Science Institute, Berkeley, California, United States of America Abstract Recent clinical evidence suggests important role of lipid and amino acid metabolism in early pre-autoimmune stages of type 1 diabetes pathogenesis. We study the molecular paths associated with the incidence of insulitis and type 1 diabetes in the Non-Obese Diabetic (NOD) mouse model using available gene expression data from the pancreatic tissue from young pre- diabetic mice. We apply a graph-theoretic approach by using a modified color coding algorithm to detect optimal molecular paths associated with specific phenotypes in an integrated biological network encompassing heterogeneous interaction data types. In agreement with our recent clinical findings, we identified a path downregulated in early insulitis involving dihydroxyacetone phosphate acyltransferase (DHAPAT), a key regulator of ether phospholipid synthesis. The pathway involving serine/threonine-protein phosphatase (PP2A), an upstream regulator of lipid metabolism and insulin secretion, was found upregulated in early insulitis. Our findings provide further evidence for an important role of lipid metabolism in early stages of type 1 diabetes pathogenesis, as well as suggest that such dysregulation of lipids and related increased oxidative stress can be tracked to beta cells. ˇ ˇ Citation: Lindfors E, Gopalacharyulu PV,