ERC FUNDED PROJECTS

For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route. To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation: Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome. Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function. Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach. Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.

1 500 000 €

Start date: 2015-04-01, End date: 2020-03-31

The goal of 2D-TOPSENSE is to exploit the remarkable stretchability of two-dimensional semiconductors to fabricate optoelectronic devices where strain is used as an external knob to tune their properties. While bulk semiconductors tend to break under strains larger than 1.5%, 2D semiconductors (such as MoS2) can withstand deformations of up to 10-20% before rupture. This large breaking strength promises a great potential of 2D semiconductors as ‘straintronic’ materials, whose properties can be adjusted by applying a deformation to their lattice. In fact, recent theoretical works predicted an interesting physical phenomenon: a tensile strain-induced semiconductor-to-metal transition in 2D semiconductors. By tensioning single-layer MoS2 from 0% up to 10%, its electronic band structure is expected to undergo a continuous transition from a wide direct band-gap of 1.8 eV to a metallic behavior. This unprecedented large strain-tunability will undoubtedly have a strong impact in a wide range of optoelectronic applications such as photodetectors whose cut-off wavelength is tuned by varying the applied strain or atomically thin light modulators. To date, experimental works on strain engineering have been mostly focused on fundamental studies, demonstrating part of the potential of 2D semiconductors in straintronics, but they have failed to exploit strain engineering to add extra functionalities to optoelectronic devices. In 2D-TOPSENSE I will go beyond the state of the art in straintronics by designing and fabricating optoelectronic devices whose properties and performance can be tuned by means of applying strain. 2D-TOPSENSE will focus on photodetectors with a tunable bandwidth and detectivity, light emitting devices whose emission wavelength can be adjusted, light modulators based on 2D semiconductors such as transition metal dichalcogenides or black phosphorus and solar funnels capable of directing the photogenerated charge carriers towards a specific position.

1 930 437 €

Start date: 2018-03-01, End date: 2023-02-28

Climate change and the decreasing availability of fossil fuels require society to move towards sustainable and renewable resources. 2DNanoCaps will focus on electrochemical energy storage, specifically supercapacitors. In terms of performance supercapacitors fill up the gap between batteries and the classical capacitors. Whereas batteries possess a high energy density but low power density, supercapacitors possess high power density but low energy density. Efforts are currently dedicated to move supercapacitors towards high energy density and high power density performance. Improvements have been achieved in the last few years due to the use of new electrode nanomaterials and the design of new hybrid faradic/capacitive systems. We recognize, however, that we are reaching a newer limit beyond which we will only see small incremental improvements. The main reason for this being the intrinsic difficulty in handling and processing materials at the nano-scale and the lack of communication across different scientific disciplines. I plan to use a multidisciplinary approach, where novel nanomaterials, existing knowledge on nano-scale processing and established expertise in device fabrication and testing will be brought together to focus on creating more efficient supercapacitor technologies. 2DNanoCaps will exploit liquid phase exfoliated two-dimensional nanomaterials such as transition metal oxides, layered metal chalcogenides and graphene as electrode materials. Electrodes will be ultra-thin (capacitance and thickness of the electrodes are inversely proportional), conductive, with high dielectric constants. Intercalation of ions between the assembled 2D flakes will be also achievable, providing pseudo-capacitance. The research here proposed will be initially based on fundamental laboratory studies, recognising that this holds the key to achieving step-change in supercapacitors, but also includes scaling-up and hybridisation as final objectives.

1 501 296 €

Start date: 2011-10-01, End date: 2016-09-30

Parkinson’s disease (PD) is the second most common neurodegenerative disorder primarily caused by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN). Despite the advances in gene discovery associated with PD, the knowledge of the PD pathogenesis is largely limited to the involvement of these genes in the generic cell death pathways, and why degeneration is specific to DA neurons and why the degeneration is progressive remain enigmatic. Broad goal of our work is therefore to elucidate the mechanisms underlying specific and progressive DA neuron degeneration in PD. Our new Drosophila model of PD ⎯Fer2 gene loss-of-function mutation⎯ is unusually well suited to address these questions. Fer2 mutants exhibit specific and progressive death of brain DA neurons as well as severe locomotor defects and short life span. Strikingly, the death of DA neuron is initiated in a small cluster of Fer2-expressing DA neurons and subsequently propagates to Fer2-negative DA neurons. We therefore propose a novel two-step model of the neurodegeneration in PD: primary cell death occurs in a specific subset of dopamindegic neurons that are genetically defined, and subsequently the failure of the neuronal connectivity triggers and propagates secondary cell death to remaining DA neurons. In this research, we will test this hypothesis and investigate the underlying molecular mechanisms. This will be the first study to examine circuit-dependency in DA neuron degeneration. Our approach will use a combination of non-biased genomic techniques and candidate-based screening, in addition to the powerful Drosophila genetic toolbox. Furthermore, to test this hypothesis beyond the Drosophila model, we will establish new mouse models of PD that exhibit progressive DA neuron degeneration. Outcome of this research will likely revolutionize the understanding of PD pathogenesis and open an avenue toward the discovery of effective therapy strategies against PD.

1 518 960 €

Start date: 2013-06-01, End date: 2018-05-31