Postdoctor in Diabetology
Type of employment: Limit of tenure, 24 months
Extent: 100 %
Location: Department of Clinical Sciences in Malm�, Malm�
First day of employment: proposed startdate 2012-06-01
Official Records Number: MPA 2012/340
Specific subject description
Cocaine and amphetamine-regulated transcript (CART) is highly expressed in brain areas controlling food intake and has gained attention since it inhibits food intake and since CART KO mice and humans with mutated CART are obese. We have shown that CART is an important islet regulatory peptide essential for maintaining normal islet function since CART KO mice exhibit diminished insulin secretion and glucose intolerance. Further, we have shown that CART is upregulated in islets of T2D patients and in rodent models of T2D CART stimulates glucose-stimulated insulin secretion (GSIS) and insulin secretion stimulated with the incretin hormone GLP-1. Therefore we conclude that absence of CART results in islet dysfunction, and that CART, on the other hand, is upregulated in beta cells when there is a need for increased insulin production. Based on this knowledge we performed genetic analyses of the impact of polymorphisms in the CARTPT gene on parameters of glucose homeostasis. This resulted in evidence for that CART is an important regulator of glucose homeostasis and part of T2D pathophysiology in humans. The receptor for CART is still not identified. Using 2-D gel technology and MS-MS we have identified 3 putative binding partners to CART in INS-1 (832/13) cells. The CART receptor is a potential drug target for obesity- and T2D therapy and identification of the receptor would be an important step towards CART-based therapies.
Aims of the project:
1) Evaluate putative CART receptor candidates.
2) Investigate if CART reduces glucagon secretion in human islets and in vivo in mice. 3) Dissect the mechanism behind the protective effects of CART against glucotoxicity. 4) Examine how beta cell overexpression of CART affects metabolism in vivo.
Methodology: Studies will be performed in clonal beta cells and rodent tissue explants, in vivo proof of concept experiment in diabetic animal models, translational studies of the function of CART in human tissues in vitro. Tools at hand are CART-adenoviral vectors, CART siRNA, CART-transgenic mice and CART KO mice.
Work environment: The lab (headed by Nils Wierup) is situated at Clinical Research Centre at the Scania University Hospital in Malm� in southern Sweden. The lab is part of the Lund University Diabetes Centre, one of the strongest constellations for diabetes research in the world. The post doc will work closely in a team with two PhD-students and one technician. In addition the post doc will team up with a network of collaborators within LUDC with expertise in cell signaling, genetics, molecular genetics, patch clamp and metabolomics.
A strong background in the diabetes field, proven knowledge in insulin and glucagon secretion mechanisms, skills in molecular biology, animal handling, confocal imaging and histology. Excellence in the English language (written and spoken) is a prerequisite.
The applicant should have an exam in molecular biology, biomedicine, medicine or similar.
The application should include: CV, publication list with top 5 publications indicated, personal letter, reference letter from at least one internationally recognized senior scientist, diplomas of university degree and high school grades.
The applications will be ranked by 3 external and internal reviewers, enabling selection of a top group of 5 candidates. At least two of these will be called for interview. Since teamwork is crucial for the success of the project special emphasis will be put on the outcome of the interview.
Basis of Assessment
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