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Project
Development and clinical validation of biological markers for beta cell destruction in vivo (FWOAL634)
Type 1 diabetes can be cured by transplantation of insulin-producing beta cells. Major problem today is that ±50% of grafted cells die shortly after implantation. Further optimization of transplant- and immune-regulatory protocols requires clinical tests that can quantify the amount of beta cell destruction. Our team has developed a highly-sensitive time-resolved fluorescence immunoassay that detects a rise of beta cell-biomarker protein GAD65 in plasma of rodents and humans shortly after transplantation.
In rodents, higher GAD65 discharge predicts poorer metabolic outcome, associated to more extensive graft destruction. Our first aim is to evaluate if this assay also predicts metabolic outcome in human beta cell graft-recipients. A second aim is to further increase its sensitivity to monitor later-stage graft rejection where more subtle waves of beta cell death are expected.
Major drawback of GAD65 as biomarker is that many patients produce anti-GAD65 auto-antibodies that interfere with marker clearance and detection. Our third aim is to identify novel biomarkers for beta cell death using a step-wise approach involving: "bottom-up" LC-MS proteomics on human beta cells, antibody-based validation of marker specificity in situ and marker discharge by dying cells in vitro. For promising candidates, sandwich immunoassays or affinity-capture targeted-SRM-MS methods will be developed.
In rodents, higher GAD65 discharge predicts poorer metabolic outcome, associated to more extensive graft destruction. Our first aim is to evaluate if this assay also predicts metabolic outcome in human beta cell graft-recipients. A second aim is to further increase its sensitivity to monitor later-stage graft rejection where more subtle waves of beta cell death are expected.
Major drawback of GAD65 as biomarker is that many patients produce anti-GAD65 auto-antibodies that interfere with marker clearance and detection. Our third aim is to identify novel biomarkers for beta cell death using a step-wise approach involving: "bottom-up" LC-MS proteomics on human beta cells, antibody-based validation of marker specificity in situ and marker discharge by dying cells in vitro. For promising candidates, sandwich immunoassays or affinity-capture targeted-SRM-MS methods will be developed.
Date:1 Jan 2012 → 31 Dec 2015
Keywords:Cell Therapy, Prevention, Transplantation, Diagnostic Tests, Immunology, Cell Death and Survival, Islet Cell Pathology, Islet Cell Biology, Beta Cell Transplantation, Diabetes
Disciplines:Basic sciences, Biological sciences