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GRK 1302:  The PI3K Pathway in Tumour Growth and Diabetes

Subject Area Medicine
Term from 2006 to 2015
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 12447501
 
Final Report Year 2017

Final Report Abstract

Phosphatidylinositol-3-kinase (PI3K) regulates crucial biological processes including cell survival, apoptosis, autophagy, metabolism and cell migration. Alterations of this central pathway are essentially involved in tumorigenesis. PI3K controls also nutrient uptake and cellular metabolism and thereby plays an important role in the pathogenesis of diabetes. Understanding this complexity of PI3K signaling necessitates broad interdisciplinary approaches in order to successfully address the urgent questions of this research field and to open up new possibilities for therapeutic intervention. The research goal of the iRTG-1302 was to study novel aspects of the PI3K signaling path-way and its contribution to tumor growth and diabetes, with a particular emphasis in exploring common themes and cross-talks involved in both pathologies. In addition, a training goal was to provide broad and modern education to doctoral students in cancer and diabetes research by combining innovative approaches in an interdisciplinary way. To this end, an interactive network was established combining Tübingen's expertise in tumor biology, physiology, cell biology, molecular medicine, pharmacology, clinical oncology and diabetology with the University of Dundee and its expertise in protein phosphorylation, kinase signaling and mouse genetics. The scientific surplus value of the mutual interaction between Tübingen and Dundee relied in the complementation of a genuine expertise. Students of the IRTR-1302 clearly benefitted from the truly interdisciplinary expertise. The integrated training and qualification program allowed them to gain an outstanding research qualification in the various disciplines. Moreover, the temporary exchange of students with the partner laboratories and excellent research facilities at both sites provided the students with additional know-how of modern techniques and allowed them to perform their interdisciplinary research projects on a clearly international level. By this way, a total of 42 funded and associated students were supported by the iRTG-1302, many of whom subsequently found excellent research positions in academia or industry. The IRTG was also highly successful from a scientific point of view. PI3K is typically activated by receptor tyrosine kinases, such as the insulin receptor, or G-protein-coupled receptors. Following this event, PI3K activates various downstream effector kinases such as PDK1, AKT and SGK. The iRTG-1302 has contributed significantly to a further understanding of PI3K signaling by identifying new kinase substrates and downstream targets, including other kinases, ion channels, transport molecules and transcription factors. Projects of the iRTG-1302 also elucidated novel upstream regulatory events in PI3K/PDK1 signaling as well as novel loops in the intense crosstalk between PI3K and the RAS/MAPK pathway. Moreover, a deeper understanding of the role of PI3K signaling in fundamental processes, such as apoptosis, senescence and autophagy, was gained by the iRTG. By controlling these processes in both diabetes and cancer, dysregulation of PI3K was found to crucially regulate drug and insulin resistance in both normal and transformed cells. Drugs targeting the PI3K pathway have emerged as highly promising tumor treatments. Indeed, during the course of this IRTG PI3K signaling emerged as a principal control pathway of metabolic reprograming and proliferation processes, which has recently opened up unexpected new mechanistic links between inflammation, obesity and cancer formation. Based on the success of the iRTG, Tübingen has therefore initiated several new research networks studying these links between metabolism, the microbiome and malignancy.

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