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Unraveling Principles of PDZ-mediated Cell Signaling

Periodic Reporting for period 2 - PDZnet (Unraveling Principles of PDZ-mediated Cell Signaling)

Reporting period: 2018-09-01 to 2020-08-31

PDZ domains are abundant protein and lipid recognizing modules that function as central organizers and regulators of dynamic cell signaling processes. In conjunction with cell membrane proteins, proteins comprising PDZ domains facilitate transmission of extracellular information into physiological output. PDZnet has been an ambitious PhD training network that brought together cutting-edge life sciences disciplines, ranging from chemical synthesis of PDZ domain modulators to studies in live animals with the overarching aim of gaining fundamental insight into the role of the PDZ interactome in cell biology and human physiology. PDZnet conducted basic research that advanced our understanding of how PDZ domain proteins act as cellular motherboards that orchestrate signaling pathways, including recognition, differentiation and integration of extracellular stimuli into appropriate cellular responses. The PDZnet research thereby aimed to shed light on the molecular machinery that is fundamental to life. While the immediate translational perspectives of a project like PDZnet can be challenging to grasp, the insights obtained from our work might in fact pave the way for advancing the utilization of PDZ domains as relevant therapeutic intervention points in major age- associated pathological conditions including cancer, stroke and Alzheimer’s disease. Despite recent intensive drug development efforts, poor treatment opportunities remain a common denominator for these rapidly growing diseases. By bringing together leading academic and industrial experts, PDZnet has enhanced the awareness of PDZ domains as novel therapeutic targets and may stipulate a paradigm-shift in industrial drug discovery programs. Potential drug candidates ascending from the PDZnet research will benefit the aging European population and the European economy, which is overburdened by increasing healthcare costs. Finally, each of the individual 14 PhD fellows will benefit from a highly structured, innovative and interdisciplinary training that has enhanced their future career perspectives and their contribution to progressing human knowledge.
We have been working with the exploration of PDZ-mediated signalling pathways as a principle for the treatment of cancer and diseases of the nervous system. This involves targeting and exploring protein- protein interactions (PPI) pathways as well as unravelling intracellular protein signalling networks related to nervous system diseases and cancer.
In general, the project has been a great success: It has been very well organized, and the training of the ESRs have been of very high quality, and essentially followed the plan as laid out in the original application with only minor adjustments. The project has led to a high number of high quality publications and even patent applications, one which is currently in discussion for licensing from the university. Moreover, several publications have recently been submitted and a significant number of additional publications is expected with the next 6 months. Altogether, these results have been obtained through extensive collaboration across the network facilitated by the ESRs.
The research has been highly complementary and covers a broad reange of disciplines from chemical sythesis to studies in animals. The research have already resulted in a large number of publications in a wide range of research areas covering oncology, molecular and cell biology, allergy and stem cells. It is foreseen that the efforts of the network in the longer term will result in a new and deeper understanding of protein protein interactions and the mechanisms influenicing them. The results have thus provided fundamental insight into important biological function with relevance for diseases, and we already see licensing interest for some of these results.