ERC FUNDED PROJECTS

Cell volume regulation is crucial for any living cell because changes in volume determine the metabolic activity through e.g. changes in ionic strength, pH, macromolecular crowding and membrane tension. These physical chemical parameters influence interaction rates and affinities of biomolecules, folding rates, and fold stabilities in vivo. Understanding of the underlying volume regulatory mechanisms has immediate application in biotechnology and health, yet these factors are generally ignored in systems analyses of cellular functions. My team has uncovered a number of mechanisms and insights of cell volume regulation. The next step forward is to elucidate how the components of a cell volume regulatory circuit work together and control the physicochemical conditions of the cell. I propose construction of a synthetic cell in which an osmoregulatory transporter and mechanosensitive channel form a minimal volume regulatory network. My group has developed the technology to reconstitute membrane proteins into lipid vesicles (synthetic cells). One of the challenges is to incorporate into the vesicles an efficient pathway for ATP production and maintain energy homeostasis while the load on the system varies. We aim to control the transmembrane flux of osmolytes, which requires elucidation of the molecular mechanism of gating of the osmoregulatory transporter. We will focus on the glycine betaine ABC importer, which is one of the most complex transporters known to date with ten distinct protein domains, transiently interacting with each other. The proposed synthetic metabolic circuit constitutes a fascinating out-of-equilibrium system, allowing us to understand cell volume regulatory mechanisms in a context and at a level of complexity minimally needed for life. Analysis of this circuit will address many outstanding questions and eventually allow us to design more sophisticated vesicular systems with applications, for example as compartmentalized reaction networks.

2 247 231 €

Start date: 2015-07-01, End date: 2020-06-30

The goal of this project is to demonstrate that novel aspects of the molecular basis of Darwinian adaptation can be discovered if the polygenic basis of adaptation is taken into account. This project will use the genome-wide distribution of cis-regulatory variants to discover the molecular pathways that are optimized during adaptation via accumulation of small effect mutations. Current approaches include scans for outlier genes with strong population genetics signatures of selection, or large effect QTL associating with fitness. They can only reveal a small subset of the molecular changes recruited along adaptive paths. Here, instead, the distribution of small effect mutations will be used to make inferences on the targets of polygenic adaptation across divergent populations in each of the two closely related species, A. thaliana and A. lyrata. These species are both found at diverse latitudes and show sign of local adaptation to climatic differences. Mutations affecting cis-regulation will be identified in leaves of plants exposed to various temperature regimes triggering phenotypic responses of adaptive relevance. Their distribution in clusters of functionally connected genes will be quantified. The phylogeographic differences in the distribution of the mutations will be used to disentangle neutral from adaptive clusters of functionally connected genes in each of the two species. This project will identify the molecular pathways subjected collectively to natural selection and provide a completely novel view on adaptive landscapes. It will further examine whether local adaptation occurs by convergent evolution of molecular systems in plants. This approach has the potential to find broad applications in ecology and agriculture.

1 683 120 €

Start date: 2015-09-01, End date: 2020-08-31

A major challenge in contemporary traffic and transportation theory is having a comprehensive understanding of pedestrians and cyclists behaviour. This is notoriously hard to observe, since sensors providing abundant and detailed information about key variables characterising this behaviour have not been available until very recently. The behaviour is also far more complex than that of the much better understood fast mode. This is due to the many degrees of freedom in decision-making, the interactions among slow traffic participants that are more involved and far less guided by traffic rules and regulations than those between car-drivers, and the many fascinating but complex phenomena in slow traffic flows (self-organised patterns, turbulence, spontaneous phase transitions, herding, etc.) that are very hard to predict accurately. With slow traffic modes gaining ground in terms of mode share in many cities, lack of empirical insights, behavioural theories, predictively valid analytical and simulation models, and tools to support planning, design, management and control is posing a major societal problem as well: examples of major accidents due to bad planning, organisation and management of events are manifold, as are locations where safety of slow modes is a serious issue due to interactions with fast modes. This programme is geared towards establishing a comprehensive theory of slow mode traffic behaviour, considering the different behavioural levels relevant for understanding, reproducing and predicting slow mode traffic flows in cities. The levels deal with walking and cycling operations, activity scheduling and travel behaviour, and knowledge representation and learning. Major scientific breakthroughs are expected at each of these levels, in terms of theory and modelling, by using innovative (big) data collection and experimentation, analysis and fusion techniques, including social media data analytics, using augmented reality, and remote and crowd sensing.

2 458 700 €

Start date: 2015-11-01, End date: 2020-10-31

Endothelial cells comprise the inner cellular cover of the vasculature, which delivers metabolites and oxygen to the tissue. Dysfunction of endothelial cells as it occurs during aging or metabolic syndromes can result in atherosclerosis, which can lead to myocardial infarction or stroke, whereas pathological angiogenesis contributes to tumor growth and diabetic retinopathy. Thus, endothelial cells play central roles in pathophysiological processes of many diseases including cardiovascular diseases and cancer. Many studies explored the regulation of endothelial cell functions by growth factors, but the impact of epigenetic mechanisms and particularly the role of novel non-coding RNAs is largely unknown. More than 70 % of the human genome encodes for non-coding RNAs (ncRNAs) and increasing evidence suggests that a significant portion of these ncRNAs are functionally active as RNA molecules. Angiolnc aims to explore the function of long ncRNAs (lncRNAs) and particular circular RNAs (circRNAs) in the endothelium. LncRNAs comprise a heterogenic class of RNAs with a length of > 200 nucleotides and circRNAs are generated by back splicing. Angiolnc is based on the discovery of novel endothelial hypoxia-regulated lncRNAs and circRNAs by next generation sequencing. To begin to understand the potential functions of lncRNAs in the endothelium, we will study two lncRNAs, named Angiolnc1 und Angiolnc2, as prototypical examples of endothelial cell-enriched lncRNAs that are regulated by oxygen levels. We will further dissect the epigenetic mechanisms, by which these lncRNAs regulate endothelial cell function. In the second part of the application, we will determine the regulation and function of circRNAs, which may act as molecular sponges in the cytoplasm. Finally, we will study the function of identified lncRNAs and circRNAs in mouse models and measure their expression in human specimens in order to determine their role as therapeutic targets or diagnostic tools.

2 497 398 €

Start date: 2016-01-01, End date: 2020-12-31