ERC FUNDED PROJECTS

Despite that C–H functionalization represents a paradigm shift from the standard logic of organic synthesis, the selective activation of non-functionalized alkanes has puzzled chemists for centuries and is always referred to one of the remaining major challenges in chemical sciences. Alkanes are inert compounds representing the major constituents of natural gas and petroleum. Converting these cheap and widely available hydrocarbon feedstocks into added-value intermediates would tremendously affect the field of chemistry. For long saturated hydrocarbons, one must distinguish between non-equivalent but chemically very similar alkane substrate C−H bonds, and for functionalization at the terminus position, one must favor activation of the stronger, primary C−H bonds at the expense of weaker and numerous secondary C-H bonds. The goal of this work is to develop a general principle in organic synthesis for the preparation of a wide variety of more complex molecular architectures from saturated hydrocarbons. In our approach, the alkane will first be transformed into an alkene that will subsequently be engaged in a metal-catalyzed hydrometalation/migration sequence. The first step of the sequence, ideally represented by the removal of two hydrogen atoms, will be performed by the use of a mutated strain of Rhodococcus. The position and geometry of the formed double bond has no effect on the second step of the reaction as the metal-catalyzed hydrometalation/migration will isomerize the double bond along the carbon skeleton to selectively produce the primary organometallic species. Trapping the resulting organometallic derivatives with a large variety of electrophiles will provide the desired functionalized alkane. This work will lead to the invention of new, selective and efficient processes for the utilization of simple hydrocarbons and valorize the synthetic potential of raw hydrocarbon feedstock for the environmentally benign production of new compounds and new materials.

2 499 375 €

Start date: 2018-11-01, End date: 2023-10-31

The study of synthetic molecular networks is of fundamental importance for understanding the organizational principles of biological systems and may well be the key to unraveling the origins of life. In addition, such systems may be useful for parallel synthesis of molecules, implementation of catalysis via multi-step pathways, and as media for various applications in nano-medicine and nano-electronics. We have been involved recently in developing peptide-based replicating networks and revealed their dynamic characteristics. We argue here that the structural information embedded in the polypeptide chains is sufficiently rich to allow the construction of peptide 'Systems Chemistry', namely, to facilitate the use of replicating networks as cell-mimetics, featuring complex dynamic behavior. To bring this novel idea to reality, we plan to take a unique holistic approach by studying such networks both experimentally and via simulations, for elucidating basic-principles and towards applications in adjacent fields, such as molecular electronics. Towards realizing these aims, we will study three separate but inter-related objectives: (i) design and characterization of networks that react and rewire in response to external triggers, such as light, (ii) design of networks that operate via new dynamic rules of product formation that lead to oscillations, and (iii) exploitation of the molecular information gathered from the networks as means to control switching and gating in molecular electronic devices. We believe that achieving the project's objectives will be highly significant for the development of the arising field of Systems Chemistry, and in addition will provide valuable tools for studying related scientific fields, such as systems biology and molecular electronics.

1 500 000 €

Start date: 2010-10-01, End date: 2015-09-30

The creation of new molecular entities and subsequent exploitation of their properties is central to a broad spectrum of research disciplines from medicine to materials. Most –if not all- of the efforts of organic chemists were directed to the development of creative strategies to built carbon-carbon and carbon-heteroatom bonds in a predictable and efficient manner. But is the creation of new bonds the only approach that organic chemistry should follow? Could we design the synthesis of challenging molecular skeleton no more through the construction of carbon-carbon bonds but rather through selective cleavage of carbon-carbon bonds (C-C bond activation)? The goal of this work is to develop powerful synthetic approaches for the selective C-C bond activation and demonstrate that it has the potential to be a general principle in organic synthesis for the regio-, diastereo- and even enantiomerically enriched preparation of adducts despite that C-C single bonds belong among the least reactive functional groups in chemistry. The realization of this synthetic potential requires the ability to functionalize selectively one C-C bond in compounds containing many such bonds and an array of functional groups. This site selective C-C bond activation is one of the greatest challenges that must be met to be used widely in complex-molecular synthesis. To emphasize the practicality of C-C bond activation, we will prepare in a single-pot operation challenging molecular framework possessing various stereogenic centers from very simple starting materials through selective C-C bond activation. Ideally, alkenes will be in-situ transformed into alkanes that will subsequently undergo the C-C activation even in the presence of functional group. This work will lead to ground-breaking advances when non-strained cycloalkanes (cyclopentane, cyclohexane) will undergo this smooth C-C bond activation with friendly and non toxic organometallic species.

2 367 495 €

Start date: 2013-11-01, End date: 2018-10-31

This research investigates a new measure that arises in information theory called directed information. Recent advances, including our preliminary results, shows that directed information arises in communication as the maximum rate that can be transmitted reliably in channels with feedback. The directed information is multi-letter expression and therefore very hard to optimize or compute. Our plan is first of all to find an efficient methodology for optimizing the measure using the dynamic programming framework and convex optimization tools. As an important by-product of finding the fundamental limits is finding coding schemes that achieves the limits. Second, we plan to find new roles for directed information in communication, especially in networks with bi-directional communication and in data compression with causal conditions. Third, encouraged by a preliminary work on interpretation of directed information in economics and estimation theory, we plan to show that directed information has interpretation in additional fields such as statistical physics. We plan to show that there is duality relation between different fields with causal constraints. Due to the duality insights and breakthroughs in one problem will lead to new insights in other problems. Finally, we will apply directed information as a statistical inference of causal dependence. We will show how to estimate and use the directed information estimator to measure causal inference between two or more process. In particular, one of the questions we plan to answer is the influence of industrial activities (e.g., $\text{CO}_2$ volumes) on the global warming. Our main focus will be to develop a deeper understanding of the mathematical properties of directed information, a process that is instrumental to each problem. Due to their theoretical proximity and their interdisciplinary nature, progress in one problem will lead to new insights in other problems. A common set of mathematical tools developed in

1 224 600 €

Start date: 2013-08-01, End date: 2019-07-31

Optical microscopy, perhaps the most important tool in biomedical investigation and clinical diagnostics, is currently held back by the assumption that it is not possible to noninvasively image microscopic structures more than a fraction of a millimeter deep inside tissue. The governing paradigm is that high-resolution information carried by light is lost due to random scattering in complex samples such as tissue. While non-optical imaging techniques, employing non-ionizing radiation such as ultrasound, allow deeper investigations, they possess drastically inferior resolution and do not permit microscopic studies of cellular structures, crucial for accurate diagnosis of cancer and other diseases. I propose a new kind of microscope, one that can peer deep inside visually opaque samples, combining the sub-micron resolution of light with the penetration depth of ultrasound. My novel approach is based on our discovery that information on microscopic structures is contained in random scattered-light patterns. It breaks current limits by exploiting the randomness of scattered light rather than struggling to fight it. We will transform this concept into a breakthrough imaging platform by combining ultrasonic probing and modulation of light with advanced digital signal processing algorithms, extracting the hidden microscopic structure by two complementary approaches: 1) By exploiting the stochastic dynamics of scattered light using methods developed to surpass the diffraction limit in optical nanoscopy and for compressive sampling, harnessing nonlinear effects. 2) Through the analysis of intrinsic correlations in scattered light that persist deep inside scattering tissue. This proposal is formed by bringing together novel insights on the physics of light in complex media, advanced microscopy techniques, and ultrasound-mediated imaging. It is made possible by the new ability to digitally process vast amounts of scattering data, and has the potential to impact many fields.

1 500 000 €

Start date: 2016-04-01, End date: 2021-03-31

"I propose to combine analytical studies and simulations to explore fundamental open questions in the dynamics and statistical mechanics of stars near massive black holes. These directly affect key issues such as the rate of supply of single and binary stars to the black hole, the growth and evolution of single and binary massive black holes and the connections to the evolution of the host galaxy, capture of stars around the black hole, the rate and modes of gravitational wave emission from captured compact objects, stellar tidal heating and destruction, and the emergence of ""exotic"" stellar populations around massive black holes. These processes have immediate observational implications and relevance in view of the huge amounts of data on massive black holes and galactic nuclei coming from earth-bound and space-borne telescopes, from across the electromagnetic spectrum, from cosmic rays, and in the near future also from neutrinos and gravitational waves."

880 000 €

Start date: 2008-09-01, End date: 2013-08-31

Glycobiology is poised to be the next revolution in biology and medicine; however, technical difficulties in detecting and characterizing glycans prevent many biologists from entering this field, thus hampering new discoveries and innovations. Herein, we propose developing a conceptually novel technology that will allow straightforward identification of specific glycosylation patterns in biofluids and in live cells. Distinct glycosylation states will be differentiated by developing “artificial noses” in the size of a single molecule, whereas selectivity toward particular glycoproteins will be obtained by attaching them to specific protein binders. To achieve high sensitivity and accuracy, several innovations in molecular recognition and fluorescence signalling are integrated into the design of these unconventional molecular analytical devices. One of the most important motivations for developing these sensors lies in their potential to diagnose a variety of diseases in their early stages. For example, we describe ways by which prostate cancer could be rapidly and accurately detected by a simple blood test that analyzes the glycosylation profile of the prostate-specific antigen (PSA). Another exceptional feature of these molecular analytical devices is their ability to differentiate between glycosylation patterns of specific proteins in live cells. This will solve an immense challenge in analytical glycobiology and will allow one to study how glycosylation contributes to diverse cell-signalling pathways. Finally, in the context of molecular-scale analytical devices, the proposed methodology is exceptional. We will show how “artificial noses” can be designed to target nanometric objects (e.g. protein surfaces) and operate in confined microscopoic spaces (e.g. cells), which macroscopic arrays cannot address. Taken together, we expect that the proposed technology will break new ground in medical diagnosis, cell biology, and biosensing technologies.

1 398 429 €

Start date: 2013-10-01, End date: 2018-09-30

The large-scale assembly of nanowires (NWs) with controlled orientation on surfaces remains one challenge toward their integration into practical devices. A recent paper in Science from the PI’s group reported the guided growth of millimeter-long horizontal NWs with controlled orientations on crystal surfaces. The growth directions and crystallographic orientation of GaN NWs are controlled by their epitaxial relationship with different planes of sapphire, as well as by a graphoepitaxial effect that guides their growth along surface steps and grooves. Despite their interaction with the surface, these horizontally grown NWs have surprisingly few defects, exhibiting optical and electronic properties superior to those of vertically grown NWs. We observed that whereas in a 2D film stress accumulates in two directions, in a NW stress accumulates along its axis, but can relax in the transversal direction, making the 1D system much more tolerant to mismatch than a 2D film. This new 1D nanoscale effect, along with the graphoepitaxial effect, subverts the paradigm not only in the young field of NWs, but also in the established field of epitaxy. This paves the way to highly controlled semiconductor structures with potential applications not available by other means. The aim of this project is to investigate the guided growth of NWs and unleash its vast possibilities toward the realization of self-integrating nanosystems. First, we will generalize the guided growth of NWs to a variety of semiconductors and substrates, and produce ordered arrays of NWs with coherently modulated composition and doping. Second, we will conduct fundamental studies to investigate the correlated structure, growth mechanism, optical and electronic properties of guided NWs. Third, we will exploit the guided growth of NWs for the production of various functional self-integrating systems, including nanocircuits, LEDs, lasers, photovoltaic cells, photodetectors, photonic and nonlinear optical devices.

2 063 872 €

Start date: 2014-02-01, End date: 2019-01-31

Inorganic nanotubes (INT) and particularly inorganic fullerene-like materials (IF) from 2-D layered compounds, which were discovered in the PI laboratory 16 years ago, are now in commercial use as solid lubricants (www.apnano.com) with prospects for numerous applications, also as part of nanocomposites, optical coatings, etc. The present research proposal capitalizes on the leadership role of the PI and recent developments in his laboratory, much of them not yet published. New synthetic approaches will be developed, in particular using the WS2 nanotubes as a template for the growth of new nanotubes. This include, for example PbI2@WS2 or WS2@NbSe2 core-shell nanotubes, which could not be hitherto synthesized. Other physical synthetic approaches like ablation with solar-light, or pulsed laser ablation will be used as well. Nanooctahedra of MoS2 (NbS2), which are probably the smallest IF (hollow cage) structures, will be synthesized, isolated and studied. Extensive ab-initio calculations will be used to predict the structure and properties of the new INT and IF nanoparticles. Cs-corrected transmission electron microscopy will be used to characterize the nanoparticles. In particular, atomic resolution bright field electron tomography will be developed during this study and applied to the characterization of the INT and IF nanoparticles. The optical, electrical and mechanical properties of the newly sythesized INT and IF materials will be investigated in great detail. Devices based on individual nanotubes will be (nano)fabricated and studied for variety of applications, including mechanical and gas sensors, radiation detectors, etc. Low temperature measurements of the transport properties of individual INT and IF will be performed.

1 618 238 €

Start date: 2008-12-01, End date: 2014-02-28

"Living organisms are sophisticated self-assembled structures that exist and operate far from thermodynamic equilibrium and, as such, represent the ultimate example of dissipative self-assembly. They remain stable at highly organized (low-entropy) states owing to the continuous consumption of energy stored in ""chemical fuels"", which they convert into low-energy waste. Dissipative self-assembly is ubiquitous in nature, where it gives rise to complex structures and properties such as self-healing, homeostasis, and camouflage. In sharp contrast, nearly all man-made materials are static: they are designed to serve a given purpose rather than to exhibit different properties dependent on external conditions. Developing the means to rationally design dissipative self-assembly constructs will greatly impact a range of industries, including the pharmaceutical and energy sectors. The goal of the proposed research program is to develop novel principles for designing dissipative self-assembly systems and to fabricate a range of dissipative materials based on these principles. To achieve this goal, we will employ novel, unconventional approaches based predominantly on integrating organic and colloidal-inorganic building blocks. Specifically, we will (WP1) drive dissipative self-assembly using chemical reactions such as polymerization, oxidation of sugars, and CO2-to-methanol conversion, (WP2) develop new modes of intrinsically dissipative self-assembly, whereby the activated building blocks are inherently unstable, and (WP3&4) conceive systems whereby self-assembly is spontaneously followed by disassembly. The proposed studies will lead to new classes of ""driven"" materials with features such as tunable lifetimes, time-dependent electrical conductivity, and dynamic exchange of building blocks. Overall, this project will lay the foundations for developing new synthetic dissipative materials, bringing us closer to the rich and varied functionality of materials found in nature."

1 999 572 €

Start date: 2019-01-01, End date: 2023-12-31

Photovoltaics and liquid fuels are poised as major contributors to the global energy market, promising cleaner, renewable sources of energy than fossil fuels. However, the technologies required to make this possibility a reality are limited by their high cost per kWh, and current share of photovoltaics and liquid fuels in the energy market is thus extremely small. One method of reducing the costs of photovoltaics lies in the use of semiconductor nanocrystals to absorb and convert solar photon energy to usable electricity and liquid fuel. Among the advantages of a nanocrystal-based design for photovoltaics are the requirement for thinner absorbing layers, the less energy-intensive refining processes, and their scalability with respect to photovoltaic production. To address these challenges, I plan to initiate a multidisciplinary research project that comprises three separate, but interrelated and complementary, parts that will be conducted in parallel. The first and the main part will be the preparation of novel hybrid nanostructures that have potential for PV and fuel cells applications. The second will focus on a systematic study of the fundamental processes of charge dynamics in the nanoscale regime. The materials and knowledge generated can then be applied in the third part of the project—development of PV and photoelectrochemical devices with scale-up potential for large-scale solar energy exploitation, and examination of benchmark properties (overall efficiency, I V characteristics, external quantum efficiency, hydrogen and liquid fuel production) of our new hybrid materials and devices. These properties will be used as feedback for the synthesis of more complex hybrid structures and for improving our device assembly methods and the choice of materials and/or composites for the devices.

1 500 000 €

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

Global concerns regarding the economy, environment and sustainable energy resources dictate an urgent need for the design of novel catalytic reactions. We have recently discovered novel, environmentally benign reactions catalyzed by pincer complexes, including an entirely new reaction, namely the direct coupling of alcohols with amines to produce amides and H2 (Science, 2007, 317, 790). We believe that the mechanisms of these reactions involve a new concept in catalysis: metal-ligand cooperation by aromatization-dearomatization of the ligand. Such cooperation can play key roles also in the activation of H2, C-H, and other bonds. Remarkably, we have very recently discovered a new strategy towards light-induced water splitting into H2 and O2, also based on metal-ligand cooperation in a pincer system, and have observed an unprecedented O-O bond formation process (Science, in press). The design of efficient catalytic systems for splitting water into hydrogen and oxygen, driven by sunlight, and without use of sacrificial reagents, is among the most important challenges facing science today, underpinning the potential of hydrogen as a clean, sustainable fuel. In this context, it is essential to enhance our understanding of the fundamental chemical steps involved in such processes. We plan to (a) explore the scope of bond activation and catalysis based on the new concept of metal ligand cooperation by aromatization-dearomatization (b) study the mechanism and scope of the newly discovered novel approach towards water splitting by light (c) develop novel environmentally benign catalytic reactions involving O-H, C-H and other bonds, such as anti-Markovnikov hydration of alkenes (d) develop unprecedented asymmetric catalysis using chiral cooperating ligands (e) develop new CO2 chemistry, including its hydrogenation to methanol and photolytic splitting to CO and O2. The research is expected to lead to novel catalysis, of importance to environment and sustainable energy.

1 912 018 €

Start date: 2010-04-01, End date: 2015-03-31

A major challenge in the field of optical imaging of live cells is to achieve label-free but still fully quantitative measurements, which afford high-resolution morphological and mechanical mapping at the single cell level. In particular, developing efficient, non-subjective, quantitative optical imaging technologies for cancer cell diagnosis is a challenging task. The ground-breaking goal of this research project is to establish a robust experimental toolbox for label-free optical diagnosis and monitoring of live cancer cells in-vitro and their potential of metastasis. Optical interferometry is able to provide a platform for imaging live cells quantitatively without the risk of effects caused by using external contrast agents. By overcoming critical technological barriers, I suggest novel hybrid optical interferometric approaches that provide a powerful nano-sensing tool for label-free quantitative measurement of cancer cells. This will be obtained by recording the dynamic quantitative, three-dimensional sub-nanometric structural and mechanical characterization of live cancer cells in different stages. For this aim, I will develop a novel low-noise broadband, common-path, off-axis interferometric system for sub-nanometric physical thickness and mechanical mapping of live cells in thousands of frames per second. Additionally, I will develop rapid tomographic approach for fully capturing the cell three-dimensional refractive-index distribution, as a tool to characterize cancer progression. Interferometry will be combined with multi-trap holographic optical tweezers and dielectrophoresis to enable complete cell manipulations including full rotation, imaging of non-adherent cells, and mechanical measurement validation. New set of interferometry-based quantitative parameters will be developed to enable characterization of cellular transformations, and used to characterize cancer cells with different metastasis potential, for cell lines and for circulating tumor cells.

1 916 250 €

Start date: 2016-07-01, End date: 2021-06-30

Property testing, an investigation started in [Blum, Luby and Rubinfeld, 1993], [Rubinfeld and Sudan, 1996], and [Goldreich, Goldwasser and Ron, 1996], deals with the following general question: Distinguish, using as few queries as possible, between the case where the input satisfies a certain property, and the case where the input is epsilon-far from this, i.e. the case where there is no way to make the input satisfy the given property even if it is modified in an epsilon fraction of its positions. Ideally the number of queries, i.e. the size of the portion of the input that is read by the (probabilistic) algorithm, depends only on epsilon and does not depend at all on the input length. However, algorithms that read more than a constant amount, as long as it is sublinear in the input size, are also deemed interesting. The related topic of sublinear algorithms concentrate on similar notions of approximation, but with the stronger requirement that the running time (rather than query complexity) that is less than the order of the input size. The purpose of this proposal is to investigate advanced topics in the frontier of property testing, especially with respect to the relation of the easiness of testing to other notions of complexity, and to investigate possible uses of ideas from property testing in other fields of computer science. Particular emphasis will be given to hypergraph-like models, sparse models, and models in which the description of the property in itself is represented as a graph or a combinatorial structure. The latter holds particular promise with regards to applications both inside and outside theoretical CS. Some topics going beyond testing (such as stronger testing notions, and testing-related notions from Probabilistically Checkable Proofs) will also be addressed.

963 540 €

Start date: 2008-07-01, End date: 2013-06-30

Our project aims to develop a new computer architecture that enables true in-memory processing based on a unit that can both store and process data using the same cells. This unit, called a memristive memory processing unit (mMPU), will substantially reduce the necessity to move data in computing systems, solving the two main bottlenecks exist in current computing systems, i.e., speed ('memory wall') and energy efficiency ('power wall'). Emerging memory technologies, namely memristive devices, are the enablers of the mMPU. While memristors are naturally used as memory, these novel devices can also perform logical operations using a technique we have invented called Memristor Aided Logic (MAGIC). This combination is the basis of mMPU. The goal of this research is to design a fully functional mMPU, and by that, to demonstrate a real computing system with significantly improved performance and energy efficiency. We have identified four main research tasks which must be completed to demonstrate a full system utilizing mMPU: mMPU design, system architecture and software, modeling and evaluation, and fabrication. Both memristive memory array and mMPU control will be designed and optimized for different technologies in the first objective. The second objective will deal with the different aspects of the system, including programming model, different mMPU modes of operation and their corresponding system implications, compiler and operating systems. For system evaluation, we will develop models and tools in the third objective in order to measure the performance, area and energy and to compare them to other state-of-the-art computing systems. Lastly, we will fabricate the different parts of the system to demonstrate the full system. Encouraged from our preliminary experimental results, we expect to achieve 10X improvement in performance, and 100X improvement in energy efficiency as compared to state-of-the-art von Neumann systems when working with appropriate workloads.

1 500 000 €

Start date: 2018-01-01, End date: 2022-12-31

I propose to develop sophisticated anti-tumor agents targeted particularly to the location of activity. My team has recently introduced a new family of Ti(IV) complexes that demonstrates higher activity than known compounds with substantially higher stability and defined hydrolytic behavior, properties that were found to be essential. I propose to study various derivatives and identify the parameters affecting activity, including steric and electronic effects, enantiomeric purity, ligand lability etc., and elucidation various mechanistic aspects of reactivity. More importantly, I propose to construct pH-sensitive transport units that will allow protection of the sensitive active species throughout their delivery and release only near the target location based on the variable pH conditions of different human tissues. In particular, unique spherical molecules held together by metal-ligand interactions will be prepared. The building blocks will consist of the planar ligands of C3-axis bound to three biocompatible Ti(IV) ions each with defined angles and geometry. The resulting spherical compounds will be utilized to encapsulate the active complexes and release them upon hydrolysis at the desired pH based on the pH-dependent hydrolysis pattern already established for related compounds. Preliminary calculations have confirmed the possibility of forming these compounds, which are particularly matching in their expected size to encapsulate our complexes. Larger spheres will also be prepared as cavities for larger molecules, which may be linked together for the delivery of multiple drugs. These compounds may find applications in various areas where a protected environment or delivery of sensitive compounds is required, such as in gene therapy, nano-technology, and catalysis.

1 400 000 €

Start date: 2009-10-01, End date: 2014-09-30

Lately, deep learning (DL) has become one of the most powerful machine learning tools with ground-breaking results in computer vision, signal & image processing, language processing, and many other domains. However, one of its main deficiencies is the lack of theoretical foundation. While some theory has been developed, it is widely agreed that DL is not well-understood yet. A proper understanding of the learning mechanism and architecture is very likely to broaden the great success to new fields and applications. In particular, it has the promise of improving DL performance in the unsupervised regime and on regression tasks, where it is currently lagging behind its otherwise spectacular success demonstrated in massively-supervised classification problems. A somewhat related and popular data model is based on sparse-representations. It led to cutting-edge methods in various fields such as medical imaging, computer vision and signal & image processing. Its success can be largely attributed to its well-established theoretical foundation, which boosted the development of its various ramifications. Recent work suggests a close relationship between this model and DL, although this bridge is not fully clear nor developed. This project revolves around the use of sparsity with DL. It aims at bridging the fundamental gap in the theory of DL using tools applied in sparsity, highlighting the role of structure in data as the foundation for elucidating the success of DL. It also aims at using efficient DL methods to improve the solution of problems using sparse models. Moreover, this project pursues a unified theoretical framework merging sparsity with DL, in particular migrating powerful unsupervised learning concepts from the realm of sparsity to that of DL. A successful marriage between the two fields has a great potential impact of giving rise to a new generation of learning methods and architectures and bringing DL to unprecedented new summits in novel domains and tasks.

1 499 375 €

Start date: 2017-10-01, End date: 2022-09-30

While advanced molecular biology approaches provide insight on the role of proteins in cellular processes, their ability to freely modify proteins and control their functions when desired is limited, hindering the achievement of a detailed understanding of the cellular functions of numerous proteins. At the same time, chemical synthesis of proteins allows for unlimited protein design, enabling the preparation of unique protein analogues that are otherwise difficult or impossible to obtain. However, effective methods to introduce these designed proteins into cells are for the most part limited to simple systems. To monitor proteins cellular functions and fates in real time, and in order to answer currently unanswerable fundamental questions about the cellular roles of proteins, the fields of protein synthesis and cellular protein manipulation must be bridged by significant advances in methods for protein delivery and real-time activation. Here, we propose to develop a general approach for enabling considerably more detailed in-cell study of uniquely modified proteins by preparing proteins having the following features: 1) traceless cell delivery unit(s), 2) an activation unit for on-demand activation of protein function in the cell, and 3) a fluorescence probe for monitoring the state and the fate of the protein. We will adopt this approach to shed light on the processes of ubiquitination and deubiquitination, which are critical cellular signals for many biological processes. We will employ our approach to study 1) the effect of inhibition of deubiquitinases in cancer. 2) Examining effect of phosphorylation on proteasomal degradation and on ubiquitin chain elongation. 3) Examining effect of covalent attachment of a known ligase ligand to a target protein on its degradation Moreover, which could trigger the development of new methods to modify the desired protein in cell by selective chemistries and so rationally promote their degradation.

2 500 000 €

Start date: 2019-10-01, End date: 2024-09-30