This proposal addresses the call topic ‘Advancing bioinformatics to meet biomedical and clinical needs’ (PHC-32-2014), with the focus on the standardization, dissemination and meta-analysis of cell migration data. Cell migration is the fundamental process in medically highly relevant topics, including morphogenesis, immune function, wound healing, and cancer metastasis, and the study of cell migration thus has a direct impact on major clinical applications, especially regarding personalized treatment and diagnosis. Over the last few years, cell migration research has benefited enormously from advances in methodology and instrumentation, allowing multiplexing and multi-parameter post-processing of cell migration analyses to become widely used. As cell migration studies have thus de facto become both a high-content as well as a high-throughput science, an urgent yet largely unmet bioinformatics need has emerged in the form of intra- and inter-lab data management solutions, standardization and dissemination infrastructure, and novel approaches and algorithms for meta-analysis. The central goal of this project is therefore to construct a comprehensive, open and free data exchange ecosystem for cell migration data, based on the development of extensible community standards and a robust, future-proof repository that collects, annotates and disseminates these data in the standardized formats. The standards and repository will be supported by freely available and open source tools for data management, submission, extraction and analysis. Importantly, we will also demonstrate the application of large-scale integrative data analysis from cell migration studies through two proof-of-concept studies: guiding personalized cancer treatment from patient organoids, and providing patient-specific diagnosis based on peripheral blood leukocyte motility. This work will also establish the foundation for a cell migration science-based ELIXIR Node.

Dysfunction of protein Tau is the main cause of dementia. Dementia associates with synaptic failure and sleep disturbances, but their connection remains elusive. In dementia, Tau becomes hyperphosphorylated (p-Tau) causing synaptic loss. Temperature fluctuations also associate with Tau phosphorylation, for example in hibernating animals. Intriguingly, my work demonstrates that brain temperature decreases during sleep, and further evidence suggests there are Tau-sites phosphorylated during sleep. My hypothesis is that sleep (and temperature)-induced Tau phosphorylation drives synaptic plasticity changes during sleep. To investigate this, I will map the dynamic changes in p-Tau during sleep and then delve into the mechanisms by mimicking brain temperature changes that naturally occur during sleep in human-induced neurons and mouse primary neurons. Employing genome engineering, I will interfere with p-Tau during sleep in mice in vivo and evaluate its impact on sleep, sleep-dependent synaptic plasticity and hippocampal long-term potentiation. This research challenges the notion that p-Tau solely drives disease progression, exploring a physiological function for p-Tau in regulating synaptic plasticity during sleep. The result of this project can challenge our understanding of Tau's function and open a new therapeutic avenue: the development of sleep-wake mechanisms to reverse the pathological p-Tau state observed in dementia. With my host lab's prior track record of uncovering critical insights into Tau-induced synaptic dysfunction, it stands as the perfect platform to tackle these questions. Additionally, I find myself in an ideal position, armed with exciting preliminary data that bolsters the validity of this proposal, and a robust technical and scientific background that empowers me to embark on this ambitious research journey. The plan I propose brings us closer to breakthroughs in effective dementia treatments.

Recently, an entirely novel type of bacteria has been discovered that can guide high electrical currents over centimeter-long distances through long, thin fibers embedded in the cell envelope. Recent studies by PRINGLE consortium members reveal that these protein fibers possess extraordinarRecently, an entirely novel type of bacteria has been discovered that can guide high electrical currents over centimeter-long distances through long, thin fibers embedded in the cell envelope. Recent studies by PRINGLE consortium members reveal that these protein fibers possess extraordinary electrical properties, including an electrical conductivity that exceeds that of any known biological material by orders of magnitude. The ambition of PRINGLE is to unlock the vast technological potential of this newly discovered biomaterial. To this end, we propose to utilize custom-crafted protein structures as elementary active and passive components in a new generation of biocompatible and biodegradable electronic devices. The resulting long-term technological vision is to establish a radically new type of electronics (PROTEONICS) that is entirely bio-based and CO2 neutral, and in which protein components can provide different all types of electronic functionality. PRINGLE will provide the fundamental and technological basis for PROTEONICS by (1) developing fabrication and patterning technologies for proteonic materials and nanostructures, (2) tuning the electronic properties of these proteonic materials in a fit-for-purpose manner, and (3) integrating proteonic materials as functional components into all-protein electronic devices. As such, PRINGLE-based technology could provide a significant breakthrough towards next generation electronics applications in a circular economy, opening entirely new avenues for interfacing biological systems with electronics and allowing completely new sustainable production and recycling pathways for electronic components.