ERC FUNDED PROJECTS

Integrins are transmembrane cell adhesion receptors controlling cell proliferation and migration. Our objective is to gain fundamentally novel mechanistic insight into the emerging new roles of integrins in cancer and to generate a road map of integrin dependent pathways critical in mammary gland development and integrin signalling thus opening new targets for therapeutic interventions. We will combine an in vivo based translational approach with cell and molecular biological studies aiming to identify entirely novel concepts in integrin function using cutting edge techniques and synthetic-biology tools. The specific objectives are: 1) Integrin inactivation in branching morphogenesis and cancer invasion. Integrins regulate mammary gland development and cancer invasion but the role of integrin inactivating proteins in these processes is currently completely unknown. We will investigate this using genetically modified mice, ex-vivo organoid models and human tissues with the aim to identify beneficial combinational treatments against cancer invasion. 2) Endosomal adhesomes – cross-talk between integrin activity and integrin “inside-in signaling”. We hypothesize that endocytosed active integrins engage in specialized endosomal signaling that governs cell survival especially in cancer. RNAi cell arrays, super-resolution STED imaging and endosomal proteomics will be used to investigate integrin signaling in endosomes. 3) Spatio-temporal co-ordination of adhesion and endocytosis. Several cytosolic proteins compete for integrin binding to regulate activation, endocytosis and recycling. Photoactivatable protein-traps and predefined matrix micropatterns will be employed to mechanistically dissect the spatio-temporal dynamics and hierarchy of their recruitment. We will employ innovative and unconventional techniques to address three major unanswered questions in the field and significantly advance our understanding of integrin function in development and cancer.

1 887 910 €

Start date: 2014-05-01, End date: 2019-04-30

Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.

1 999 770 €

Start date: 2018-05-01, End date: 2023-04-30

BEHAVFRICTIONS will use novel models focussing on information-processing frictions to explain choice patterns described in behavioral economics and psychology. The proposed research will provide microfoundations that are essential for (i) identification of stable preferences, (ii) counterfactual predictions, and (iii) normative conclusions. (i) Agents who face information-processing costs must trade the precision of choice against information costs. Their behavior thus reflects both their stable preferences and the context-dependent procedures that manage their errors stemming from imperfect information processing. In the absence of micro-founded models, the two drivers of the behavior are difficult to disentangle for outside observers. In some pillars of the proposal, the agents follow choice rules that closely resemble logit rules used in structural estimation. This will allow me to reinterpret the structural estimation fits to choice data and to make a distinction between the stable preferences and frictions. (ii) Such a distinction is important in counterfactual policy analysis because the second-best decision procedures that manage the errors in choice are affected by the analysed policy. Incorporation of the information-processing frictions into existing empirical methods will improve our ability to predict effects of the policies. (iii) My preliminary results suggest that when an agent is prone to committing errors, biases--such as overconfidence, confirmatory bias, or perception biases known from prospect theory--arise under second-best strategies. By providing the link between the agent's environment and the second-best distribution of the perception errors, my models will delineate environments in which these biases shield the agents from the most costly mistakes from environments in which the biases turn into maladaptations. The distinction will inform the normative debate on debiasing.

1 321 488 €

Start date: 2018-06-01, End date: 2023-05-31

"Large bodies usually follow the classical equations of motion. Deviations from this can be called macroscopic quantum behavior. These phenomena have been experimentally verified with cavity Quantum Electro Dynamics (QED), trapped ions, and superconducting Josephson junction systems. Recently, evidence was obtained that also moving objects can display such behavior. These objects are micromechanical resonators (MR), which can measure tens of microns in size and are hence quite macroscopic. The degree of freedom is their vibrations: phonons. I propose experimental research in order to push quantum mechanics closer to the classical world than ever before. I will try find quantum behavior in the most classical objects, that is, slowly moving bodies. I will use MR's, accessed via electrical resonators. Part of it will be in analogy to the previously studied macroscopic systems, but with photons replaced by phonons. The experiments are done in a cryogenic temperature mostly in dilution refrigerator. The work will open up new perspectives on how nature works, and can have technological implications. The first basic setup is the coupling of MR to microwave cavity resonators. This is a direct analogy to optomechanics, and can be called circuit optomechanics. The goals will be phonon state transfer via a cavity bus, construction of squeezed states and of phonon-cavity entanglement. The second setup is to boost the optomechanical coupling with a Josephson junction system, and reach the single-phonon strong-coupling for the first time. The third setup is the coupling of MR to a Josephson junction artificial atom. Here we will access the MR same way as the motion of a trapped ions is coupled to their internal transitions. In this setup, I am proposing to construct exotic quantum states of motion, and finally entangle and transfer phonons over mm-distance via cavity-coupled qubits. I believe within the project it is possible to perform rudimentary Bell measurement with phonons."

2 004 283 €

Start date: 2015-01-01, End date: 2019-12-31