The SYSCID consortium aims to develop a systems medicine approach for disease prediction in CID. We will focus on three major CID indications with distinct characteristics, yet a large overlap of their molecular risk map: inflammatory bowel disease, systemic lupus erythematodes and rheumatoid arthritis. We have joined 15 partners from major cohorts and initiatives in Europe (e.g.IHEC, ICGC, TwinsUK and Meta-HIT) to investigate human data sets on three major levels of resolution: whole blood signatures, signatures from purified immune cell types (with a focus on CD14 and CD4/CD8) and selected single cell level analyses. Principle data layers will comprise SNP variome, methylome, transcriptome and gut microbiome. SYSCID employs a dedicated data management infrastructure, strong algorithmic development groups (including an SME for exploitation of innovative software tools for data deconvolution) and will validate results in independent retrospective and prospective clinical cohorts. Using this setup we will focus on three fundamental aims : (i) the identification of shared and unique "core disease signatures” which are associated with the disease state and independent of temporal variation, (ii) the generation of "predictive models of disease outcome"- builds on previous work that pathways/biomarkers for disease outcome are distinct from initial disease risk and may be shared across diseases to guide therapy decisions on an individual patient basis, (iii) "reprogramming disease"- will identify and target temporally stable epigenetic alterations in macrophages and lymphocytes in epigenome editing approaches as biological validation and potential novel therapeutic tool . Thus, SYSCID will foster the development of solid biomarkers and models as stratification in future long-term systems medicine clinical trials but also investigate new causative therapies by editing the epigenome code in specific immune cells, e.g. to alleviate macrophage polarization defects.

<< Objectives >>Generate awareness of medical students on the importance and complexity of medical residencies in NeurosurgeryDesign innovative training programme for medical students Increase the level of knowledge & readiness of medical professionals to embrace with no doubt’s residencies on Neurosurgery Reduce drop-out rates of medical graduates at Neurosurgery residenciesImprove the teaching & digital skills of HE teachers and tutorsBoost the attractiveness of the educational offers in medical studies<< Implementation >>Co-development of a training programme with end-users involvement (co-design and validation sessions)Co-development of lesson plans and the resources for 25h teaching, complemented with eLearning materials (thematic lessons, tutorials, info-sheets, case studies, etc) for students autonomous work (50h)Design of a guidebook for teachers/trainersLaunch a piloting action and impact assessment of the training course, including students mobilities (80 participants; 20 students in mobility)<< Results >>A Training programme outline (learning outcomes; common standards for the training, ECTC)30 lesson plans with support resources for 25h teaching (face-to-face/synchronous) Set of eLearning materials (thematic lessons, tutorials, info-sheets, case studies, etc) covering students autonomous work (50h)Guidebook for teachers/trainersPiloting and impact assessment of the training course (80 participants)Students mobility plans (20 students) 1-week, 25h)

Microbes have remarkable capabilities to attach to surfaces of natural and artificial systems, eventually leading to the formation of biofilms and associated chronic and persistent infections. It is extremely appealing to understand how bacteria interact with three- dimensional surface topographies and how to design smart patterns as a strategy to create antifouling and biocidal materials. Here I propose a dynamic strategy, merging verstile and large-scale surface modification teqhniques based on mechanical wrinkling of soft bilayers, that I developed at Imperial College London, microfluidics and microbiology. The goal of MOBILE is investigating the mechanical confinement exerted by non-planar surface curvatures and spatial heterogeneities induced by fluid shear on bacterial initial attachment and removal, in confined environments. Specifically (Aim 1), I will evaluate the combined action of surface topography and fluid shear over bacterial proliferation, motitly and viability, incorporating nano- to micro-scaled wrinkled geometries in microfluidic channels, mimicking biological tissues surfaces and implantable medical devices, testing a series of different clinically relevant bacterial strains (such as Enterococcus faecalis, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae). I will also (Aim 2) develop antifouling and removal strategies by investigating the mechanical response of adhered bacteria, using patterned surfaces as stimuli-responsive probes "actuated" by means of mechanical deformation (i.e., by extension and compression of the wrinkled topographies) to induce detachment and surface cleaning under fluid dynamic conditions. Overall, I aim to elucidate new methodologies for bacterial removal at different stages of biofilm formation paving the way towards the development of new classes of biomedical devices and to contribute to an important step in direction of controlling implant-associated infections.

Tissue responses to microbial and endogenous danger signals involve the activation of both resident and monocyte-derived macrophages, as well as the coordinated inducible expression of hundreds of inflammatory genes. Gene transcription is controlled by the information contained in thousands of genomic regulatory elements (enhancers and promoters), which is first read by transcription factors (TFs) and then integrated and relayed to the transcriptional machinery via an array of co-regulators with disparate biochemical activities and functions. The recent work of several groups, including our own, has extensively characterized how in macrophages the genomic regulatory sequences controlling inflammatory gene expression are coordinately bound and activated by myeloid lineage-determining TFs and broadly expressed stimulus-activated TFs. However, we still have a very incomplete understanding of the necessary next step in the process, namely how distinct combinations of DNA-bound TFs regulate recruitment and function of the co-regulators and machineries that control gene transcription. Here, I propose to systematically identify the complement of co-regulators that control the induction of inflammatory genes in macrophages, which will be then mechanistically and functionally characterized both in vitro and in vivo. By integrating cutting edge genomic and computational approaches with focused genetic screens and biochemical analyses, and eventually validating relevant results in mouse models, this project aims at obtaining an unprecedented level of understanding of the information flow linking genomic regulatory elements to inflammatory gene transcription.

Immune-mediated diseases (IMIDs) are an increasing medical burden in industrialized countries worldwide. IMIDs are characterized by an enormous heterogeneity with regard to disease outcome and response to targeted therapies, which currently cannot be adequately anticipated to tailor individual patient management. Hence, mechanistic understanding of this heterogeneity and biomarkers predictive for disease control and therapy response over time are important prerequisites of a future precision medicine in IMIDs. ImmUniverse has been formed as a European transdisciplinary consortium to tackle these unmet needs and to understand the role of the crosstalk between tissue microenvironment and immune cells in disease progression and response to therapy of two different IMIDs: ulcerative colitis and atopic dermatitis. Following this unique cross-disease approach ImmUniverse will fill the gap and the limitations of current studies, which do not systematically compare the complex interactions between recirculating immune cells and the respective tissue microenvironment. The consortium will combine analysis of tissue-derived signatures with “circulating signatures” detectable in liquid biopsies, employing state-of-the-art profiling technologies corresponding to multi-Omics datasets. The project will also bring diagnostics in IMID to a new level by implementing disruptive non-invasive liquid-biopsy methodology in combination with novel, validated circulating biomarker assays which are expected to improve diagnosis, inform early in the clinical course on disease severity and progression and enable treatment response monitoring. The identified signature will be validated to monitor state/progression and response to therapy in prospective observational cohorts. Realization of these objectives will result in improvement of patient management, lead to increased patient well-being and will significantly reduce the socioeconomic burden of these diseases.