ERC FUNDED PROJECTS

Tissue homeostasis requires coordinated barrier function in blood and lymphatic vessels. Opening of junctions between endothelial cells (ECs) lining blood vessels leads to tissue fluid accumulation that is drained by lymphatic vessels. A pathological increase in blood vessel permeability or lack or malfunction of lymphatic vessels leads to edema and associated defects in macromolecule and immune cell clearance. Unbalanced barrier function between blood and lymphatic vessels contributes to neurodegeneration, chronic inflammation, and cardiovascular disease. In this proposal, we seek to gain mechanistic understanding into coordination of barrier function between blood and lymphatic vessels, how this process is altered in disease models and how it can be manipulated for therapeutic purposes. We will focus on two critical barriers with diametrically opposing functions, the blood-brain barrier (BBB) and the lymphatic capillary barrier (LCB). ECs of the BBB form very tight junctions that restrict paracellular access to the brain. In contrast, open junctions of the LCB ensure uptake of extravasated fluid, macromolecules and immune cells, as well as lipid in the gut. We have identified novel effectors of BBB and LCB junctions and will determine their role in adult homeostasis and in disease models. Mouse genetic gain and loss of function approaches in combination with histological, ultrastructural, functional and molecular analysis will determine mechanisms underlying formation of tissue specific EC barriers. Deliverables include in vivo validated targets that could be used for i) opening the BBB on demand for drug delivery into the brain, and ii) to lower plasma lipid uptake via interfering with the LCB, with implications for prevention of obesity, cardiovascular disease and inflammation. These pioneering studies promise to open up new opportunities for research and treatment of neurovascular and cardiovascular disease.

2 499 969 €

Start date: 2019-07-01, End date: 2024-06-30

Diatoms are major contributors of primary production in the ocean and participate in carbon sequestration over geologically relevant timescales. As key components of the Earth’s carbon cycle and marine food webs we need to understand the eco-evolutionary underpinnings of their ecological success to forecast their fate in a future ocean impacted by anthropogenic change. Genomes and epigenomes from model diatoms, as well as hundreds of transcriptomes from multiple species, have revealed genetic and epigenetic processes regulating gene expression in response to changing environments. The Tara Oceans survey has in parallel generated resources to explore diatom abundance, diversity and gene expression in the world’s ocean in widely contrasting conditions. DIATOMIC will build on these resources to understand how evolutionary and ecological processes combine to influence diatom adaptations to their environment at unprecedented spatiotemporal scales. To examine these processes over timescales relevant to current climate change, DIATOMIC includes the pioneering exploration of ancient diatom DNA from the sub-seafloor to reveal the genetic and epigenetic bases of speciation and adaptation that have impacted their ecological success during the last 100,000 years, when Earth experienced major climatological events and an increase in anthropogenic impacts. As a model for exploring eco-evolutionary processes in the past and contemporary ocean we will focus primarily on Chaetoceros because this diatom genus is ancient, ubiquitous, abundant and contributes significantly to carbon export. Key findings will be additionally supported by lab-based studies using the diatom Phaeodactylum for which exemplar molecular tools exist. Specifically, the project will address: 1. What molecular features characterize genome evolution in diatoms? 2. Which processes determine diatom metapopulation structure? 3. What can ancient DNA tell us about diatom adaptations to environmental change in the past?

2 495 753 €

Start date: 2019-11-01, End date: 2024-10-31

The overall aim of the IMMUNOTHROMBOSIS project is to clarify the mechanisms underlying the recently identified synergism between thrombosis and inflammation. Thrombus formation and inflammation are vital host responses that ensure homeostasis, but can also drive cardiovascular disease, including myocardial infarction and stroke, the major causes of death in Europe. My group and others discovered, that thrombosis and inflammation are not to be considered separate processes. They are tightly interrelated and synergize in immune defence, but also in inflammatory and thrombotic diseases in a process we termed immunothrombosis. Targeting this synergism has great potential to identify innovative and unconventional strategies to more specifically prevent undesired activation of thrombotic and inflammatory pathways. However, this requires a deeper mechanistic understanding of immunothrombosis. I recently identified two ground-breaking novel immunothrombotic principles: I discovered that platelets have the ability to migrate autonomously, which assists immune cells in fighting pathogens. Further, I revealed that immune cells play a central role in controlling the production of platelets from their megakaryocyte precursors. The physiological and pathophysiological relevance of both processes is unclear. This is the starting point and focus of the IMMUNOTHROMBOSIS project. My aim is to define how platelets use their ability to migrate to support immune cells in protection of vascular integrity (objective 1) and to identify the contribution of platelet migration to different cardiovascular diseases involving immunothrombotic tissue damage (objective 2). Finally, I will clarify how inflammatory responses feedback to the production of thrombotic effectors and dissect inflammatory mechanisms that control platelet production (objective 3). IMMUNOTHROMBOSIS will identify new options for specific prevention or treatment of thrombotic and inflammatory cardiovascular diseases.

2 321 416 €

Start date: 2019-09-01, End date: 2024-08-31

Time series characterize diverse systems, examples in this proposal are: i) Proton motion in an inhomogeneous aqueous environment, ii) folding and unfolding of a peptide described by a suitably chosen reaction coordinate, iii) migration of a living cell on a substrate, iv) US Dollar / Yen exchange rate. Examples i) and ii) are close-to-equilibrium, iii) is a far from equilibrium since energy is constantly dissipated, while example iv) at first sight defies the classification into equilibrium or non-equilibrium. For the understanding, comparison, classification and forecasting of time series data, stochastic differential equations, diverse random walk models, and more recently, machine-learning algorithms are commonly used. But fundamental questions remain unanswered: Is a unified description of such diverse systems possible? What is the relation between different proposed models? Can the non-equilibrium degree of a time series be estimated? NoMaMemo provides a unified description of generic time series data in terms of non-linear integro-differential stochastic equations based on memory functions that are extracted from data. NoMaMemo accounts for non-linear and non-equilibrium effects as well as for non-Gaussian noise and connects with fundamental concepts such as equilibrium statistical mechanics, response theory and entropy production. The general formulation contains previously proposed models and thus allows their comparison, forecasting quality will be compared with modern machine-learning algorithms. NoMaMemo creates a generic platform to analyse, understand, compare, classify and predict time series data and to optimize stochastic systems with respect to search efficiency, barrier-crossing speed or other figures of merit. NoMaMemo will significantly advance the understanding of chemical reaction and protein folding kinetics, the interpretation of THz and IR spectroscopy of liquids and the analysis of living matter and socio-economic data.

1 983 744 €

Start date: 2019-12-01, End date: 2024-11-30