ERC FUNDED PROJECTS

Advanced insight into ever smaller structures of matter and their ever faster dynamics hold promise for pushing the frontiers of many fields in science and technology. Time-domain investigations of ultrafast microscopic processes are most successfully carried out by pump/probe experiments. Intense waveform-controlled few-cycle near-infrared laser pulses combined with isolated sub-femtosecond XUV (extreme UV) pulses have made possible direct access to electron motion on the atomic scale. These tools along with the techniques of laser-field-controlled XUV photoemission (“attosecond streaking”) and ultrafast UV-pump/XUV-probe spectroscopy have permitted real-time observation of electronic motion in experiments performed on atoms in the gas phase and of electronic transport processes in solids. The purpose of this project is to to get insight into intra- and inter-molecular electron dynamics by extending attosecond spectroscopy to these processes. AEDMOS will allow control and real-time observation of a wide range of hyperfast fundamental processes directly on their natural, i.e. attosecond (1 as = EXP-18 s) time scale in molecules and molecular structures. In previous work we have successfully developed attosecond tools and techniques. By combining them with our experience in UHV technology and target preparation in a new beamline to be created in the framework of this project, we aim at investigating charge migration and transport in supramolecular assemblies, ultrafast electron dynamics in photocatalysis and dynamics of electron correlation in high-TC superconductors. These dynamics – of electronic excitation, exciton formation, relaxation, electron correlation and wave packet motion – are of broad scientific interest reaching from biomedicine to chemistry and physics and are pertinent to the development of many modern technologies including molecular electronics, optoelectronics, photovoltaics, light-to-chemical energy conversion and lossless energy transfer.

1 999 375 €

Start date: 2015-05-01, End date: 2020-04-30

A technological revolution is currently taking place making it possible to noninvasively study metabolism in mammals (incl. humans) in vivo with unprecedented temporal and spatial resolution. Central to these developments is the phenomenon of hyperpolarization, which transiently enhances the magnetic resonance (MR) signals so much that real-time metabolic imaging and spectroscopy becomes possible. The first clinical translation of hyperpolarization MR technology has recently been demonstrated with prostate cancer patients. I have played an active role in these exciting developments, through design and construction of hyperpolarization MR setups that are defining the cutting-edge for in vivo preclinical metabolic studies. However, important obstacles still exist for the technology to fulfill its enormous potential. With this highly interdisciplinary proposal, I will overcome the principal drawbacks of current hyperpolarization technology, namely: 1) A limited time window for hyperpolarized MR detection; 2) The conventional use of potentially toxic polarizing agents; 3) The necessity to use supra-physiological doses of metabolic substrates to reach detectable MR signal I will develop a novel hyperpolarization instrument making use of photoexcited compounds as polarizing agents to produce hyperpolarized solutions containing exclusively endogenous compounds. It will become possible to deliver hyperpolarized solutions in a quasi-continuous manner, permitting infusion of physiological doses and greatly increasing sensitivity. I will also use a complementary isotope imaging technique, the so-called CryoNanoSIMS (developed at my institution over the last year), which can image isotopic distributions in frozen tissue sections and reveal the localization of injected substrates and their metabolites with subcellular spatial resolution. Case studies will include liver and brain cancer mouse models. This work is pioneering and will create a new frontier in molecular imaging.

2 199 146 €

Start date: 2016-09-01, End date: 2021-08-31

Autophagy, a lysosomal degradation pathway in which the cell digests its own components, is an essential biological pathway that promotes organismal health and longevity and helps combat cancer and neurodegenerative diseases. Accordingly, the 2016 Nobel Prize in Physiology or Medicine was awarded for research in autophagy. Although autophagy has been extensively studied from yeast to mammals, the molecular events that underlie its induction and progression remain elusive. A highly conserved protein kinase, Atg1, plays a unique and essential role in initiating autophagy, yet despite this pivotal importance it has taken over twenty years for its first downstream target to be discovered. However, whilst our identification of the autophagy related membrane protein Atg9 as the first Atg1 substrate is an important advance, the molecular mechanisms that enable the extensive remodelling of cellular membranes that occurs during autophagy is still completely undefined. A detailed knowledge of the inputs and outputs of the Atg1 kinase will enable us to provide a definitive mechanistic understanding of autophagy. We have devised a novel permeabilized cell assay that reconstitutes the pathway in vitro, allowing us to recapitulate key steps in the autophagic process and thereby determine how the individual steps that lead up to autophagy are controlled. We will use this system to dissect the functional role of Atg1 kinase in autophagosome-vacuole fusion (Objective 1), and to determine the origin of the autophagic membrane and the role of Atg1 in expanding these (Objective 2). To reveal how Atg1/ULK1 kinase is activated in mammalian cells, we will apply the unique and carefully tailored synthetic in vivo approaches that we have recently developed (Objective 3). By focusing on the activation of the Atg1 kinase and the molecular events that it executes, we will be able to explain its central role in regulating the autophagic process and define the mechanistic steps in the pathway.

1 955 666 €

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

Many significant global challenges in catalysis for energy and sustainable chemistry have already been solved in nature. Metalloenzymes within microorganisms catalyse the transformation of carbon dioxide into simple carbon building blocks or fuels, the reduction of dinitrogen to ammonia under ambient conditions and the production and utilisation of dihydrogen. Catalytic sites for these reactions are necessarily based on metals that are abundant in the environment, including iron, nickel and molybdenum. However, attempts to generate biomimetic catalysts have largely failed to reproduce the high activity, stability and selectivity of enzymes. Proton and electron transfer and substrate binding are all finely choreographed, and we do not yet understand how this is achieved. This project develops a suite of new experimental infrared (IR) spectroscopy tools to probe and understand mechanisms of redox metalloenzymes in situ during electrochemically-controlled steady state turnover, and during electron-transfer-triggered transient studies. The ability of IR spectroscopy to report on the nature and strength of chemical bonds makes it ideally suited to follow the activation and transformation of small molecule reactants at metalloenzyme catalytic sites, binding of inhibitors, and protonation of specific sites. By extending to the far-IR, or introducing mid-IR-active probe amino acids, redox and structural changes in biological electron relay chains also become accessible. Taking as models the enzymes nitrogenase, hydrogenase, carbon monoxide dehydrogenase and formate dehydrogenase, the project sets out to establish a unified understanding of central concepts in small molecule activation in biology. It will reveal precise ways in which chemical events are coordinated inside complex multicentre metalloenzymes, propelling a new generation of bio-inspired catalysts and uncovering new chemistry of enzymes.

1 997 286 €

Start date: 2019-03-01, End date: 2024-02-29