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CORE; Programme area: health; ID: 196258

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Project title: Role of the FTO dioxygenase in development of obesity - multidisciplinary study on selected model systems

 

Acronym: FTO

 

Project Promoter: Institute of Biochemistry And Biophysics Polish Academy od Sciences

 

Polish partners: Warsaw University of Life Sciences – Faculty of Veterinary Medicine

 

Norwegian Partners: Oslo University Hospital, Department of Molecular Biology, Institute of Microbiology

 

Project cost (EUR): 954 932

 

Grant amount (EUR): 954 932

Duration: 42 months

 

 

www: http://www.ibb.waw.pl/pl/Sekretariat%20Naukowy/Projekty%20strukturalne/fto

 

 

Project summary:

Obesity, diabetes and hypoxia during sleep apnea are multi-gene lifestyle diseases that have presently become a social problem in many societies. Two members of the AlkB dioxygenase superfamily, FTO and ALKBH5 proteins are connected with obesity development and hypoxia, respectively. Human genome-wide searches have identified a strong association of single nucleotide polymorphisms (SNPs) in the FTO gene with adiposity and increased body mass index (BMI), obesity and type 2 diabetes risk. In this study we will focus on FTO and ALKBH5 protein purification and complex formation, recognition of a link between genotype and FTO content in saliva, presence of FTO in mammalian tissues and liquids, and its localization in different organs. We will evaluate the usefulness of ALKBH5 levels as a hypoxia biomarker. Mutant mice models will be crucial to determine the role of ALKBH5 and FTO and to identify altered methylation patterns in gene-targeted mice. Further analysis of 6-methyladenine (6mA), a major substrate for both, ALKBH5 and FTO will be performed. The effect of stomach surgery on FTO regulation will be studied on two models, insulin resistant rats after bariatric surgery and saliva from bariatric patients. Biochemical characterization of FTO and ALKBH5 hydroxylation activity will be done to identify their new substrates. Molecular backgrounds of substrate specificity and structure of FTO and ALKBH5 will be supported by in silico modelling and cross-link/LC-MS analyses. All biological materials and results obtained during the project realization will be exchanged accordingly to the laboratory specialization. This is a unique opportunity to analyse one sample with sophisticated approaches available in our Consortium laboratories specializing in a variety of modern techniques. Our experienced team of experts and young scientists willresolve the role of FTO and ALKBH5 proteins in the development of above mentioned diseases.

 

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