Objective Rationale - Insulin dependent diabetes (IDDM) is an autoimmune disease which destroys insulin-producing pancreatic b^ta-cells. Europe, with one million patients, shows areas with highest incidence. IDDM has devastating vascular complications with staggering costs; neither cure nor prevention is available. The aetiology of IDDM is poorly understood. The events allowing escape from immune tolerance to islet auto antigens are unknown; an early islet dysfunction could be directly involved. The effector mechanisms for b^ta-cell destruction also remain elusive. It has been accepted that b^ta-cells are slowly destroyed; this is uncertain, and it is not known to what extent b^ta-cell loss can be compensated bybêta-cell regeneration. These key issues must be solved to design strategies to prevent IDDM or replace the b^ta-cell mass. Ex vivo expansion of native orsurrogate bêta-cells, while technically feasible, have been unsuccessful due to dedifferentiation of engineered cells. Solving these problems may revolutionise IDDM treatment.Objectives - Six European research groups with expertise in the fields of diabetes immunology, bêta-cell biology, insulin gene expression, gene transfer technology and islet transplantation here design a holistic approach to IDDMaetiology with the aim of developing concepts and techniques towards noveldiabetes treatments.Objective 1 is to understand the role of bêta-cell dysfunction and dysregulation of islet antigen presentation in autoimmunity. We will determine the exact role that bêta-cells play in the initiation of the autoimmune process. We propose that neuroimmune dysregulation of is letfunction augments presentation of bêta-cell antigens, these will be identified with islet specific T cell clones.Objective 2 is to clarify the mechanisms of bêta-cell growth and death with the aim of developing strategies for promoting resistance to autoimmune attack and enhancing bêta-cell repair and regeneration for preventing IDDM. The kinetics of bêta-cell destruction, the mechanisms that lead to death following cytokine exposure, mainly regulation of iNOS gene expression and molecular measures capable of attenuating it, will be studied. A protein expressed in the bêta-cell, reg, can prevent IDDM in NOD mice, its effect invivo, and in transfection experiments in vitro will be clarified.Objective 3 aims at engineering glucose-sensitive bêta-and non-bêta-cells towards ex vivo gene therapy in IDDM. Methods are developed to induce conditional immortalization of bêta-cells with methotrexate-inducible degron vectors. We identified the transcription factor that controls insulin gene expression and transmits stimulation byglucose; its regulation will be clarified and its gene introduced together with insulin gene into heterologous cells to create glucose-sensitive "artificial bêta-cells". These will be tested in vitro and in vivo for function and immune recognition. To achieve these objectives, Core Facility Centres have been established for developing tools to assess antigen expression and recognition (Paris), for gene transfer tools and techniques (Milan), and for engineering insulin-producing cells (Jerusalem).Innovative Potential - This integrative approach is unique and promises that key questions on the aetiology and pathophysiology of IDDM will be answered. Major effort will be invested in molecular methods for modifying bêta-cell survival and creating substrates for cell therapy in IDDM. These can lead to novel therapies in diabetes and will therefore be extremely attractive to the European pharmaceutical industry. Fields of science medical and health sciencesmedical biotechnologygenetic engineeringgene therapymedical and health sciencesbasic medicinephysiologypathophysiologymedical and health sciencesclinical medicineendocrinologydiabetesmedical and health sciencesbasic medicineimmunologyautoimmune diseasesmedical and health sciencesmedical biotechnologycells technologies Programme(s) FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998 Topic(s) 4.4.2 - Insulin and non-insulin diabetes Call for proposal Data not available Funding Scheme CSC - Cost-sharing contracts Coordinator HADASSAH MEDICAL ORGANIZATION Address Hadassah university hospital 91120 Jerusalem Israel See on map EU contribution € 0,00 Participants (5) Sort alphabetically Sort by EU Contribution Expand all Collapse all CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE France EU contribution € 0,00 Address Rue de sèvres 161 université paris v 75743 Paris See on map Erasmus Universiteit Rotterdam Netherlands EU contribution € 0,00 Address 50,dr. molewaterplein 3015 GE Rotterdam See on map Fondazione Centro San Raffaele del Monte Tabor - Istituto di Ricovero e Cura a Carattere Scientifico Italy EU contribution € 0,00 Address Via olgettina 58 20132 Milano See on map Institut National de la Santé et de la Recherche Médicale France EU contribution € 0,00 Address 82,avenue denfert rochereau 75674 Paris See on map Vrije Universiteit Brussel Belgium EU contribution € 0,00 Address 103,laarbeeklaan 1090 Bruxelles See on map
