ERC FUNDED PROJECTS

The interest on autophagy, an evolutionarily conserved process in eukaryotes, has enormously increased in the last years, since autophagy is involved in many diseases such as cancer and neurodegenerative disorders. Autophagosome formation is the key process in autophagy. Despite extensive work, the model of autophagosome formation is not yet well established. Some important questions on autophagosome biogenesis remain to be elusive, such as where the bona fide marker protein of autophagosome, LC3, is lipidated, how lipidated LC3 functions in autophagosome formation, and how the proteins for LC3 lipidation and delipidation are involved in autophagosome formation. Although genetic approaches have been useful to identify genes involved in autophagy, they are chronic and thereby the dynamics of phenotypic change cannot be followed, making them not suited for study highly dynamic process such as autophagosome formation. Herein, I propose to develop and use novel chemical probes to address these issues. First, I plan to prepare semi-synthetic caged LC3 proteins and apply them to monitor dynamics of autophagosome formation in the cell in order to address those questions on autophagosome formation. The semi-synthetic LC3 proteins are expected to confer a temporal control and to realize manipulation of protein structure, which renders such studies possible. Second, I intend to develop a versatile approach targeting specific endogenous proteins using a reversible chemically induced dimerization (CID) system, termed as “knock on and off” strategy. I plan to use this approach to elucidate the function of two distinct PI3K complexes in autophagosome formation. On one hand, the establishment of novel approaches will open up a new avenue for studying biological processes. On the other hand, the use of the tool will reveal the mechanism of autophagy.

1 500 000 €

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

Space benefits mankind through the services it provides to Earth. Future space activities progress thanks to space transfer and are safeguarded by space situation awareness. Natural orbit perturbations are responsible for the trajectory divergence from the nominal two-body problem, increasing the requirements for orbit control; whereas, in space situation awareness, they influence the orbit evolution of space debris that could cause hazard to operational spacecraft and near Earth objects that may intersect the Earth. However, this project proposes to leverage the dynamics of natural orbit perturbations to significantly reduce current extreme high mission cost and create new opportunities for space exploration and exploitation. The COMPASS project will bridge over the disciplines of orbital dynamics, dynamical systems theory, optimisation and space mission design by developing novel techniques for orbit manoeuvring by “surfing” through orbit perturbations. The use of semi-analytical techniques and tools of dynamical systems theory will lay the foundation for a new understanding of the dynamics of orbit perturbations. We will develop an optimiser that progressively explores the phase space and, though spacecraft parameters and propulsion manoeuvres, governs the effect of perturbations to reach the desired orbit. It is the ambition of COMPASS to radically change the current space mission design philosophy: from counteracting disturbances, to exploiting natural and artificial perturbations. COMPASS will benefit from the extensive international network of the PI, including the ESA, NASA, JAXA, CNES, and the UK space agency. Indeed, the proposed idea of optimal navigation through orbit perturbations will address various major engineering challenges in space situation awareness, for application to space debris evolution and mitigation, missions to asteroids for their detection, exploration and deflection, and in space transfers, for perturbation-enhanced trajectory design.

1 499 021 €

Start date: 2016-08-01, End date: 2021-07-31

The Standard Model of Particle Physics describes the fundamental components of ordinary matter and their interactions. Despite its success in predicting many experimental results, the Standard Model fails to account for a number of interesting phenomena. One phenomenon of particular interest is the large excess of unobservable (Dark) matter in the Universe. This excess cannot be explained by Standard Model particles. A compelling hypothesis is that Dark Matter is comprised of particles that can be produced in the proton-proton collisions from the Large Hadron Collider (LHC) at CERN. Within this project, I will build a team of researchers at Lund University dedicated to searches for signals of the presence of Dark Matter particles. The discovery strategies employed seek the decays of particles that either mediate the interactions between Dark and Standard Model particles or are produced in association with Dark Matter. These new particles manifest in detectors as two, three, or four collimated jets of particles (hadronic jets). The LHC will resume delivery of proton-proton collisions to the ATLAS detector in 2015. Searches for new, rare, low mass particles such as Dark Matter mediators have so far been hindered by constraints on the rates of data that can be stored. These constraints will be overcome through the implementation of a novel real-time data analysis technique and a new search signature, both introduced to ATLAS by this project. The coincidence of this project with the upcoming LHC runs and the software and hardware improvements within the ATLAS detector is a unique opportunity to increase the sensitivity to hadronically decaying new particles by a large margin with respect to any previous searches. The results of these searches will be interpreted within a comprehensive and coherent set of theoretical benchmarks, highlighting the strengths of collider experiments in the global quest for Dark Matter.

1 268 076 €

Start date: 2016-02-01, End date: 2021-07-31

Epigenetic alterations can be detected in all cancers and in essentially every patient. Despite their prevalence, the concrete functional roles of these alterations are not well understood, for two reasons: First, cancer samples tend to carry many correlated epigenetic alterations, making it difficult to statistically distinguish relevant driver events from those that co-occur for other reasons. Second, we lack tools for targeted epigenome editing that could be used to validate biological function in perturbation and rescue experiments. The proposed project strives to overcome these limitations through experimental and bioinformatic methods development, with the ambition of making and breaking cancer cells in vitro by introducing defined sets of epigenetic alterations. We will focus on leukemia as our “model cancer” (given its low mutation rate, frequent defects in epigenetic regulators, and availability of excellent functional assays), but the concepts and methods are general. In Aim 1, we will generate epigenome profiles for a human knockout cell collection comprising 100 epigenetic regulators and use the data to functionally annotate thousands of epigenetic alterations observed in large cancer datasets. In Aim 2, we will develop an experimental toolbox for epigenome programming using epigenetic drugs, CRISPR-assisted recruitment of epigenetic modifiers for locus-specific editing, and cell-derived guide RNA libraries for epigenome copying. Finally, in Aim 3 we will explore epigenome programming (methods from Aim 2) of candidate driver events (predictions from Aim 1) with the ultimate goal of converting cancer cells into non-cancer cells and vice versa. In summary, this project will establish a broadly applicable methodology and toolbox for dissecting the functional roles of epigenetic alterations in cancer. Moreover, successful creation of a cancer that is driven purely by epigenetic alterations could challenge our understanding of cancer as a genetic disease.

1 281 205 €

Start date: 2016-12-01, End date: 2021-11-30