Objective
The objectives of the project are to: 1. develop highly competent insulin-secreting cell lines by genetic engineering. Such cells should respond to glucose as promptly and consistently as normal pancreatic beta-cells and should have high insulin content. 2. develop and optimise methods for micro-encapsulation of the engineered cells for protecting against immune damage; characterise conditions for growth and survival of beta-cells in the microcapsules.3. characterise mechanisms of signalling that mediates secretion in the native and the engineered cells before and after micro-encapsulation 4. transplant diabetic animals with highly competent insulin-secreting cells encapsulated in immune barrier and study the effects of such procedures on diabetic status and on the transplanted cells.
A hallmark of the approach would be to manipulate GLP-l- and CAMPmediated signalling pathways to increase competence of beta-cells.
Background works from the coordinator's laboratory establish critical role of CAMP system and the incretin hormone GLP-l in regulating stimulus-secretion coupling in pancreatic beta cells. Several of the currently available beta cell lines do respond to physiological range of glucose concentration but not as promptly and as consistently as does the normal beta cells. In the proposed project we shall engineer cells to stably express proglucagon which would be processed to GLP-l within the beta-cells and the engineered cells would secrete insulin and GLP-l. The latter would make beta cells competent by an autocrine interaction as well as provide GLP-l for other physiological functions. Variations of the approach namely expression of a constitutively active mutant of stimulatory subunit of G protein and a constitutively active mutant of GLP-l receptor will be pursued in the project. The response and insulin content will be further improved by iterative engineering with transfection of insulin and glucokinase gene as need be . The cells will be made resistant to apoptosis by expression of bc12. The engineered cells will be micro-encapsulated using modifications of methods for immunoisolation. The effects of engineering and encapsulations will be characterised by studying effects on growth, survival, secretion and cellular mechanisms of signalling. Finally the cells will be transplanted to murine diabetic models to assess the effects on diabetic status and performance of the cells under in-vivo conditions.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences medical biotechnology genetic engineering
- natural sciences biological sciences biochemistry biomolecules proteins
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
171 76 STOCKHOLM
Sweden
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.