Touch sensation is built upon the ability of sensory neurons to detect and transduce nanometer scale mechanical displacements. The underlying process has been termed mechanotransduction: the high sensitivity and speed of which is enabled by direct gating (opening) of ion channels by mechanical force. Force detection is functionally compartmentalized and only takes place at the peripheral endings of sensory neurons in vivo. Two molecules are known to be genetically necessary for touch in many sensory neurons, the force gated ion channel PIEZO2 and its modulator STOML3. However, mechanotransduction complexes in all touch receptors absolutely require tethering to the extracellular matrix for function. Tethering is dependent on large extracellular proteins that are sensitive to site-specific proteases. Here we will not only identify the nature of these tethers, but will develop technology to acutely and reversibly abolish tethers and other mechanotransducer components. We will use genome engineering to tag tether and mechanotranduction components in order to visualize and manipulate these proteins at their in vivo sites of action. By engineering de novo cleavage sites for site-specific proteases we will render tethers and ion channels newly sensitive to normally ineffective proteases in the skin. We will engineer mutations into candidate ion channels that dramatically alter biophysical properties to physiologcally “mark” function in vivo. Finally we will develop new behavioural paradigms in mice that allow us to measure touch perception from the forepaw. Psychometric curves for different vibrotactile tasks can then be precisely compared between humans and mice. Furthermore, the impact of acute and reversible manipulation of mechanotransduction on touch perception can be measured. Understanding how molecules assemble to function in a mechanotransduction complex in the skin will open up avenues to develop therapeutic strategies to modulate touch.

The social and economic challenges of ageing populations and chronic disease can only be met by translation of biomedical discoveries to new, innovative and cost effective treatments. The ESFRI Biological and Medical Research Infrastructures (BMS RI) underpin every step in this process; effectively joining scientific capabilities and shared services will transform the understanding of biological mechanisms and accelerate its translation into medical care. Biological and medical research that addresses the grand challenges of health and ageing span a broad range of scientific disciplines and user communities. The BMS RIs play a central, facilitating role in this groundbreaking research: inter-disciplinary biomedical and translational research requires resources from multiple research infrastructures such as biobank samples, and resources from multiple research infrastructures such as biobank samples, imaging facilities, molecular screening centres or animal models. Through a user-led approach CORBEL will develop the tools, services and data management required by cutting-edge European research projects: collectively the BMS RIs will establish a sustained foundation of collaborative scientific services for biomedical research in Europe and embed the combined infrastructure capabilities into the scientific workflow of advanced users. Furthermore CORBEL will enable the BMS RIs to support users throughout the execution of a scientific project: from planning and grant applications through to the long-term sustainable management and exploitation of research data. By harmonising user access, unifying data management, creating common ethical and legal services, and offering joint innovation support CORBEL will establish and support a new model for biological and medical research in Europe. The BMS RI joint platform will visibly reduce redundancy and simplify project management and transform the ability of users to deliver advanced, cross-disciplinary research.

One of the most remarkable processes in biology is how animals develop from a single fertilized egg within a short time of rapid growth and an explosion in spatial and cellular diversity. Embryonic development is highly deterministic and consistent among different embryos and conserved across species. Astonishingly, embryos reuse the same signaling pathways in diverse developmental contexts to robustly pattern tissues. The advent of single-cell genomics in the last decade has allowed to chart the phenomenology of cellular differentiation at unprecedented resolution and scale. Yet, moving from such single-cell descriptions to models of how embryonic tissues achieve robustness and precision in their differentiation remains exceedingly difficult. To this end, we will develop new algorithms that will infer the spatiotemporal dynamics of differentiating tissues from space-, time- and lineage-resolved data. Tissues will be modelled as groups of proliferating and interacting cells distributed in space and moving along transcriptional, epigenetic and signaling manifolds. Focusing on the developmental stages of gastrulation and early organogenesis, we will reconstruct the spatiotemporal trajectories of cells together with the dynamics of their local niches. These trajectories will serve as the input to mathematical models that will predict local changes in a cell’s state from its signalome, epigenome and transcription factor repertoire. Using zebrafish embryos as a high-throughput system of vertebrate development, we will systematically test these models through time-dependent, combinatorial perturbations with a multiomic read-out. My overall goal is to develop quantitative, data-based models of how transcriptional, epigenetic and intercellular changes at the cellular level translate into robust and deterministic dynamics at the tissue level and to apply these methods to dissect how positional information and cell fate commitment emerges in the vertebrate embryo.

SMALL MOLECULES TO TREAT METABOLIC SYNDROME Metabolic Syndrome (MS) is defined as a cluster of inter-related symptoms including central obesity, insulin resistance, dyslipidemia, and hypertension that promote the development of type 2 diabetes mellitus, cardiovascular diseases and certain cancers. In this project a pharmacological strategy will be developed that could alleviate the vicious circle of hyperglycemia (elevated blood glucose) and elevated insulin observed in metabolic syndrome that accelerates the onset of type 2 diabetes. We have identified a new protein that participates in insulin-dependent increase in glucose uptake from the blood. Loss of this protein leads to reduced insulin dependent glucose uptake and a metabolic syndrome like disease in mice. In this project small molecules that modulate the function of the said protein will be developed and evaluated. New molecules that enhance glucose uptake into cells could be potentially powerful new tools to reverse insulin resistance a key pathology of metabolic syndrome that can accelerate the onset of type 2 diabetes.