Description
The objective of the project is to further develop the molecular basis of diseases within modern society: obesity, diabetes, and hypoxia during sleep apnea. We will characterize two proteins FTO and ALKBH5 connected with the diseases mentioned above. The recognition of a link between genotype and FTO content in mammalian tissues and liquids, and its localization in different organs, influence of bariatric operations and diet on the level of FTO and ALKBH5 protein will serve finding new approaches to obesity/diabetes/hypoxia prevention. Project realization will be possible thanks to a long term bilateral relation with donor partner, the Oslo University Hospital. We will take advantage of exchanging materials and techniques within Consortium laboratories as well as preparing common publications. Partnership achievement will be based on complementary research, further widening the knowledge on the mentioned diseases and the possibility of further cooperation. Expected target groups are the whole of society, physicians, dietetics, and pharmaceutical firms.
Summary of project results
In the light of extension of civilization diseases like cancer, obesity, type 2 diabetes, it has been of general importance to study a family of ALKBH dioxygenases with special attention to FTO and ALKBH5 proteins. We started with the FTO purification in eucariotic baculovirus system which allowed to obtain posttranslationally modified, active protein. Further, we have found that FTO is affected by Ca2+ and on the basis of HDX-MS data the model of FTO interacting with calmodulin has been proposed. Also, several small ligand like antraquinones were identified to interact with FTO and ALKBH3. The ALKBH5 and FTO relevant phenotypes has been recognized in mice. High resolution of 6meA mapping in mRNA has been done. We discovered that FTO, ALKBH5, and other three ALKBH dioxygenases (ALKBH1, 3, and 4) are overexpressed in head and neck cancer tissue. This is of great importance since it indicates possible direction of anticancer therapy by using inhibitors of these proteins. We have found such inhibitors among antraquinone derivatives, already known (rhein) or synthetized by us. We complete patent pending on the subject and prepare a manuscript submitted in Cell Metabolism. Our great achievement is using pig model (normal and IUGR) for FTO localization in tissues and its dependency on diet. We have found that FTO is highly expressed in liver and co-exists with insulin resistance and obesity related markers.
Summary of bilateral results
The cooperation between Polish and Norwegian research teams persists during 10 years and has realized two edition of Polish-Norwegian grants. During both editions we have worked on the role of ALKBH proteins, previously in bacteria, now in Eukaryote including the state of disease. Both sides have overworked new and supplementary approaches that allowed to get closer to the role of FTO/ALKBH5 proteins in development of civilization diseases such as obesity, type 2 diabetes and cancer. More specifically, the partners achieved complementary results working on different animal models (mouse/pig), and analyze phenomenon on transcriptomic and proteomic levels. The Norwegian partner is one of the world best team working since years on ALKBH dioxygenases, thus we benefit by the exchange of materials (e.g. Fto cDNA), technics (e.g. structural models of FTO and ALKBH5), and experimental approaches (e.g. FTO purification in baculovirus system). Finally, in cooperation, we prepared a manuscript that has been submitted to Cell Metabolism (if. 17). The fund allowed to exchange the knowledge and ideas during two workshops (in Warsaw and in Oslo), and Thomas Lindhal Conference (2015). Since we have not finished our scientific projects yet, we are determined to continue the cooperation.