ERC FUNDED PROJECTS

As an onco-hematologist with a strong expertise in genomics, I significantly contributed to the understanding of multiple myeloma (MM) heterogeneity and its evolution over time, driven by genotypic and phenotypic features carried by different subpopulations of cells. MM is preceded by prevalent, asymptomatic stages that may evolve with variable frequency, not accurately captured by current clinical prognostic scores. Supported by preliminary data, my hypothesis is that the same heterogeneity is present early on the disease course, and identification of the biological determinants of evolution at this stage will allow better prediction of its evolutionary trajectory, if not its control. In this proposal I will therefore make a sharp change from conventional approaches and move to early stages of MM using unique retrospective sample cohorts and ambitious prospective sampling. To identify clonal MM cells in the elderly before a monoclonal gammopathy can be detected, I will collect bone marrow (BM) from hundreds of hip replacement specimens, and analyze archive peripheral blood samples of thousands of healthy individuals with years of annotated clinical follow-up. This will identify early genomic alterations that are permissive to disease initiation/evolution and may serve as biomarkers for clinical screening. Through innovative, integrated single-cell genotyping and phenotyping of hundreds of asymptomatic MMs, I will functionally dissect heterogeneity and characterize the BM microenvironment to look for determinants of disease progression. Correlation with clinical outcome and mini-invasive serial sampling of circulating cell-free DNA will identify candidate biological markers to better predict evolution. Last, aggressive modelling of candidate early lesions and modifier screens will offer a list of vulnerabilities that could be exploited for rationale therapies. These methodologies will deliver a paradigm for the use of molecularly-driven precision medicine in cancer.

1 998 781 €

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

Nature has evolved astonishingly diverse structures where the nanoscale assembly of components is key to their functionality. Such nanostructures self-assemble at massive scales and at spatial resolutions surpassing top-down production techniques. The leaves of a single tree, e.g., can cover the area of 10.000 m^2 while every mm^2 contains more than 10^8 highly efficient light-harvesting complexes. For future photovoltaic devices, light-managing surfaces and photonic devices it will thus be beneficial to adopt principles of self-assembly. Advances in design and low-cost production of DNA nanostructures allow us to challenge nature. By combining the assembly power of bottom-up DNA origami with top-down lithography it will be possible to fabricate functional nanostructured materials designed on the molecular level while reaching macroscopic dimensions. With the goal to boost energy conversion rates, I will design DNA structures that grow from pre-patterned surfaces and assemble into interpenetrating 3D networks that exhibit the highest possible contact area for electron donor and acceptor molecules in organic photovoltaic devices. Spectral tuning through carefully designed dye arrangements will complement these efforts. Custom-tailored photonic crystals built from lattices of DNA origami structures will control the flow of light. By incorporating dynamic DNA reconfigurability and colloidal nanoparticles at freely chosen positions, intelligent materials that respond to external cues such as light or heat are projected. Positioning accuracy of 1 nm renders possible the emergence of so-called “Dirac plasmons” in DNA-assembled particle lattices. Such topologically protected states are sought after for the coherent and loss-less propagation of energy and information in next-generation all-optical circuits. These approaches have the potential to reduce production costs and increase efficiencies of light-harvesting devices, intelligent surfaces and future computing devices.

1 997 500 €

Start date: 2019-04-01, End date: 2024-03-31

Multiple Sclerosis (MS) is a leading cause of unpredictable and incurable progressive disability in young adults. Although the exact cause remains unknown, this immune-mediated disease is likely triggered by environmental factors in genetically predisposed individuals. I propose that epigenetic mechanisms, which regulate gene expression without affecting the genetic code, mediate the processes that cause MS and that aberrant epigenetic states can be corrected, spearheading the development of alternative therapies. We will exploit the stable and reversible nature of epigenetic marks, in particular DNA methylation, to gain insights into the novel modifiable disease mechanisms by studying the target organ in a way that has not been possible before. This highly ambitious project comprises three synergistic facets formulated in specific aims to: (i) identify epigenetic states that characterize the pathogenesis of MS, (ii) prioritize functional epigenetic states using high-throughput epigenome-screens, and (iii) develop novel approaches for precision medicine based on correcting causal epigenetic states. Our unique MS biobank combined with cutting-edge methodologies to capture pathogenic cells and measure their functional states provides a rational starting point to identify MS targets. I will complement this approach with studies of the functional impact of MS targets using innovative in vitro screens, with the added value of unbiased discovery of robust regulators of specific MS pathways. Finally, my laboratory has extensive experience with animal models of MS and I will utilize these powerful systems to dissect molecular mechanisms of MS targets and test the therapeutic potential of targeted epigenome editing in vivo. Our findings will set the stage for a paradigm-shift in studying and treating chronic inflammatory diseases based on preventing and modulating aggressive immune responses by inducing self-sustained reversal of aberrant epigenetic states.

1 998 798 €

Start date: 2019-06-01, End date: 2024-05-31

The very well-known concept of formal oxidation states, used e. g. for redox reactions is one of the most fundamental ones in general chemistry. However, in the area of very strong oxidizers even the familiar oxido(-II) ligand becomes redox-innocent and assigning oxidation states becomes ambiguous. Very strong (super-) oxidizers are compounds whose oxidizing strength exceeds that of elemental F2. Anyhow, not only molecular oxidizer but also their interaction with the environment in different media needs to be considered, as these dramatically affect their intrinsic oxidizing strength. Here we propose novel conjugate oxidizer/Lewis or Brønsted acid systems with extremely high ox. power. These new ox. media make use of the alliance of high ox. strength and Lewis /Brønsted super acidity. The investigation and development of oxidizers is of essential interest in all areas of chemistry and beyond. Unfortunately a detailed understanding of this fundamental chemistry is still lacking. Here we describe based on three work strands PV, MI, and BP, how we aim at a more fundamental understanding of such systems. The undertaken research, which includes qc investigations, molecular characterizations in matrices and synthetic fluorine chemistry as well as oxido complexes is summarized in five work packages describing different prototype areas (organigram). Based on the gained knowledge, the project will rank and specify such oxidizers and the mechanism leading to ox. media. By using the threefold work strand approach, our project will guide us in a systematic discovery of the systems with high application potential in terms of selectivity and disposability, and oxidizing systems with high to ultrahigh oxidation potentials, and into the chemical terra incognita of fragile molecules at the edge of stability. We envision to highlight that the outcome of the project will be extremely useful for scientists from almost all fields of chemistry and related disciplines.

1 988 280 €

Start date: 2020-01-01, End date: 2024-12-31

Immunotherapy holds the potential to dramatically improve the curative prognosis of cancer patients. However, despite significant progress, a huge gap remains to be bridged to gain board success in the clinic. A first limiting factor in cancer immunotherapy is the low response rate in large fraction of the patients and an unmet need exists for more efficient - potentially synergistic - immunotherapies that improve upon or complement existing strategies. The second limiting factor is immune-related toxicity that can cause live-threatening situations as well as seriously impair the quality of life of patients. Therefore, there is an urgent need for safer immunotherapies that allow for a more target-specific engineering of the immune system. Strategies to engineer the immune system via a materials chemistry approach, i.e. immuno-engineering, have gathered major attention over the past decade and could complement or replace biologicals, and holds promise to contribute to resolving the current issues faced by the immunotherapy field. I hypothesize that synthetic biomaterials can play an important role in anti-cancer immunotherapy with regard to synergistic, safe, but potent, instruction of innate and adaptive anti-cancer immunity and to revert the tumor microenvironment from an immune-suppressive into an immune-susceptible state. Hereto, the overall scientific objective of this proposal is to fully embrace the potential of immuno-engineering and develop several highly synergistic biomaterials strategies to engineer the immune system to fight cancer. I will develop a series of biomaterials and address a number of fundamental questions with regard to optimal biomaterial design for immuno-engineering. Based on these findings, I will elucidate those therapeutic strategies that lead to synergistic engineering of innate and adaptive immunity in combination with remodeling the tumor microenvironment from an immune-suppressive into an immune-susceptible state.

2 000 000 €

Start date: 2019-04-01, End date: 2024-03-31

InOutBioLight aims to design multifunctional rubbers with enhanced mechanical, thermal, color-converting, and light-guiding features towards advanced biohybrid lighting and photovoltaic technologies. The latter are placed at the forefront of the EU efforts for low-cost production and efficient consumption of electricity, a critical issue for a sustainable development. In this context, the use of biomolecules as functional components in lighting and photovoltaic devices is still a challenge, as they quickly denature under storage and device operation conditions. This paradigm has changed using an innovative rubber-like material, in which the biofunctionality is long preserved. As a proof-of-concept, color down-converting rubbers based on fluorescent proteins were used to design the first biohybrid white light-emitting diode (bio-HWLED). To develop a new generation of biohybrid devices, InOutBioLight will address the following critical issues, namely i) the nature of the protein-matrix stabilization, ii) how to enhance the thermal/mechanical features, iii) how to design multifunctional rubbers, iv) how to mimic natural patterns for light-guiding, and v) how to expand the technological use of the rubber approach. To achieve these goals, InOutBioLight involves comprehensive spectroscopic, microscopic, and mechanical studies to investigate the protein-matrix interaction using new polymer matrices, additives, and protein-based nanoparticles. In addition, the mechanical, thermal, and light-coupling features will be enhanced using structural biocompounds and reproducing biomorphic patterns. As such, InOutBioLight offers three major advances: i) a thorough scientific basis for the rubber approach, ii) a significant thrust of the emerging bio-HWLEDs, and iii) innovative breakthroughs beyond state-of-the-art biohybrid solar cells.

1 999 188 €

Start date: 2020-01-01, End date: 2024-12-31

"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

Cardiac toxicity is one of the most frequent serious side effects of cancer therapy, affecting up to 30% of treated patients. Cancer treatment-induced cardiotoxicity (CTiCT) can result in severe heart failure. The trade-off between cancer and chronic heart failure is an immense personal burden with physical and psychological consequences. Current therapies for CTiCT are suboptimal, featuring poor early detection algorithms and nonspecific heart failure treatments. Based on our recently published results and additional preliminary data presented here, we propose that CTiCT is associated with altered mitochondrial dynamics, triggering a cardiomyocyte metabolic reprogramming. MATRIX represents a holistic approach to tackling mitochondrial dysfunction in CTiCT. Our hypothesis is that reverting metabolic reprogramming by shifting mitochondrial substrate utilization could represent a new paradigm in the treatment of early-stage CTiCT. By refining a novel imaging-based algorithm recently developed in our group, we will achieve very early detection of myocardial damage in patients treated with commonly prescribed cancer therapies, long before clinically used parameters become abnormal. Such early detection, not available currently, is crucial for implementation of early therapies. We also hypothesize that in end-stage CTiCT, mitochondrial dysfunction has passed a no-return point, and the failing heart will only be rescued by a strategy to replenish the myocardium with fresh healthy mitochondria. This will be achieved with a radical new therapeutic option: in-vivo mitochondrial transplantation. The MATRIX project has broad translational potential, including a new therapeutic approach to a clinically relevant condition, the development of technology for early diagnosis, and advances in knowledge of basic disease mechanisms.

1 999 375 €

Start date: 2019-09-01, End date: 2024-08-31

Diabetes mellitus is characterised by hyperglycaemia caused by an absolute or relative insulin deficiency. The global prevalence of diabetes has reached more than 410 million individuals, underscoring the need for novel therapeutic strategies targeting the pathology as a multi-organ disease. Protein tyrosine phosphatases (PTPs) constitute a superfamily of enzymes that dephosphorylate tyrosine-phosphorylated proteins and oppose the actions of protein tyrosine kinases. My previous studies and preliminary data suggest that PTPs act as molecular switches for key signalling events in the development of diabetes, i.e. insulin/glucose/cytokine signalling. Dysregulation of these pathways results in metabolic consequences that are cell-specific. Oxidative stress abrogates the nucleophilic properties of the PTP active site and induces conformational changes that inhibit PTP activity and prevent substrate-binding. I have recently developed an innovative proteomic approach to quantify PTP oxidation in vivo and demonstrated that this occurs in liver/pancreas under pathological conditions, including obesity and inflammation. In this proposal, I aim to fully characterise the activity and oxidation status of PTPs in dysfunctional metabolic relevant cells in obesity and diabetes. Importantly, the crucial role of PTPs make them promising candidates for the treatment of metabolic disorders. I hypothesise that specific antioxidants, diets and/or adenovirus will restore PTP function and ameliorate the metabolic deleterious defects in pre-clinical studies. Over the next 5 years, I aim to: • Identify the major oxidised PTPs in metabolic relevant tissues/cells in both obesity and diabetes. • Determine the contribution of PTP inactivation in cellular responses to metabolic signalling in human samples. • Assess the impact of tissue-specific PTP deficiency on the development of obesity and diabetes. • Test novel therapeutic approaches targeting PTPs to prevent/reverse metabolic disorders.

1 966 906 €

Start date: 2019-04-01, End date: 2024-03-31

Each year millions of animals undertake remarkable migratory journeys, across oceans and through hemispheres, guided by the Earth’s magnetic field. While there is unequivocal behavioural evidence demonstrating the existence of the magnetic sense, it is the least understood of all sensory faculties. The biophysical, molecular, cellular, and neurological underpinnings of the sense remain opaque. In this application we aim to remedy this situation, exploiting an established assay, our unique infrastructure, and state-of-the-art methodology, using pigeons as a model system. The proposal will address three questions: 1) Where are the primary magnetosensors? 2) Where is magnetic information processed in the brain? 3) How is magnetic information encoded in the brain? In Aim 1 we will explore whether inner ear hair cells are the primary sensors, and if the detection of magnetic stimuli depends on the presence of magnetic crystals or electromagnetic induction. We will employ a range of physical methods to locate magnetite, and a molecular approach to identify putative electroreceptors. In Aim 2 we will use light sheet microscopy coupled with clearing methods to undertake whole brain mapping of magnetically-induced neuronal activation in the pigeon. We will complement these studies with transcriptomic methods to molecularly and anatomically define magnetosensitive circuits within the pigeon brain. We will build on this work in Aim 3 utilising in vivo 2-photon microscopy to investigate how cells within the pigeon brain encode magnetic information. We will determine whether neurons encode for specific components of the magnetic field (i.e. inclination, intensity, and polarity) and explore whether there are spatially restricted ensembles, providing a dynamic picture of magnetically induced neuronal activity. We anticipate that these experiments will reveal a secret that nature has kept hidden for millennia; How do animals detect magnetic fields?

1 990 376 €

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

Radiotherapy (RT) is one of the most frequently used methods for cancer treatment (above 50% of patients will receive RT). Despite remarkable advancements, the dose tolerances of normal tissues continue to be the main limitation in RT. Finding novel approaches that allow increasing normal tissue resistance is of utmost importance. This would make it possible to escalate tumour dose, resulting in an improvement in cure rate. With this aim, I propose a new approach, called proton minibeam radiation therapy (PROTONMBRT), which combines the prominent advantages of protons for RT and the remarkable tissue preservation provided by the use of submillimetric field sizes and a spatial fractionation of the dose, as in minibeam radiation therapy (MBRT). The main objectives of this project are to explore the gain of therapeutic index for radioresistant tumors, to disentangle the biological mechanisms involved and to evaluate the clinical potential of this novel approach. For this purpose, a method for minibeam generation adequate for patient treatments and a complete set of dosimetric tools will be developed. Then, tumour control effectiveness will be evaluated, and the possible biological mechanisms involved both in tumour and normal tissue responses will be disentangled. The gain in normal tissue recovery can foster one of the main applications of proton therapy, paediatric oncology, as well as open the door to an effective treatment of very radioresistant tumours, such as high-grade gliomas, which are currently mostly treated palliatively.

1 997 870 €

Start date: 2019-09-01, End date: 2024-08-31

Despite the abundance of organic compounds in Nature, only 12 contain fluorine. In contrast, fluorinated organic materials account for over 40% of all pharmaceuticals and agrochemicals. Closer inspection of the fluorination patterns in these functional molecules reveals striking extremes towards perfluorination (in both 2D and 3D scaffolds) or single site fluorination predominantly in aryl substituents. Consequently, most fluorinated moieties in functional materials lack stereochemical information and are thus achiral. This disparity between the paucity of naturally occurring organofluorine compounds and their venerable history in functional molecule design confirms the enormous potential of fluorinated materials in the discovery of novel properties. That progress has largely been confined to 3 dimensional achiral and 2 dimensional achiral architectures reflects the synthetic challenges associated with preparing stereochemical defined multiply fluorinated systems. A major limitation in the construction of C(sp3)-F units remains the need for substrate pre-functionalisation via oxidation and the competing substitution/elimination scenario that compromises efficiency in the deoxyfluorination. This problem is magnified in the synthesis of optically active fluorides where the deoxyfluorination can compromise the enantiopurity of the starting materials. The principle aim of RECON is to facilitate exploration of 3D, chiral space by providing access to multiply fluorinated, stereochemically complex organofluorine materials from simple feedstock using inexpensive, commercially available fluoride sources. In providing a modular platform to rationally place function on a structural basis, exploration of uncharted chemical space will accelerate the discovery of next generation materials for medicinal and agrochemistry, material sciences and bio-medicine.

1 999 375 €

Start date: 2019-02-01, End date: 2024-01-31

The production of chemicals, plastics, solvents, etc., contributes to 20 % of the Gross Value Added in the EU, where sales have doubled over the last 20 years. Despite this dynamism, the chemical industry is energy intensive and 95 % of organic chemicals derive from fossil oil and natural gas. To sustain the growth of this industry, the replacement of fossil feedstocks with renewable carbon, phosphorus and silicon sources should be encouraged. Nonetheless, such a sourcing shift represents a paradigm shift: while the development of petrochemistry has relied on the selective oxidation of hydrocarbons, the conversion of renewable feedstocks (e.g. CO2, phosphates, silicates or biomass) requires efficient reduction methods and catalysts to overcome their oxidized nature. Today, no reduction method meets the criteria for a versatile and energy efficient reduction of oxidized feedstocks and the aim of the ReNewHydrides project is to design novel reductants and catalytic reactions to achieve this important aim. At the crossroads of main group element chemistry, organometallic chemistry, electrochemistry and homogenous catalysis, I propose to develop innovative and recyclable reductants based on silicon and boron compounds, and to utilize them to tackle catalytic challenges in the reduction of C–O, P–O and Si–O bonds. The overarching principle is to build a balanced synthetic cycle, where the electrochemical reduction of functionalized and oxidized substrates is ensured by silicon and boron based hydride donors, with a high energy efficiency and selectivity. This project will foster innovative routes in the utilization of renewable carbon, phosphorus and silicon feedstocks. It is therefore of high risk, but ultimately extremely rewarding. The results will also also open-up new horizons in silicon and boron chemistry and they will finally serve the scientific community involved in the fields of organic and inorganic chemistry, sustainable chemistry and energy storage.

1 999 838 €

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

Schizophrenia is a heritable but genetically complex disease. Pathological and epidemiological data fit a model of SCZ as a network disease with perturbations during brain development leading to early-adulthood onset clinical symptomatology. Our present understanding is based on single markers or arrays of gene expression from tissue samples containing multiple cell types. As a consequence, pathological changes in the function of inhibitory or excitatory neurons, microglia, or oligodendrocytes have variously been proposed to be the cause of symptoms. In light of recent data I hypothesize that it is unlikely that the various cellular SCZ-pathologies all arise independently from genetic alterations in multiple cell types. Recent findings from my lab show that in the cortex the expression of risk genes for SCZ are enriched in excitatory neurons, and that this set of risk-genes is largely non-overlapping with those expressed in other cell types. I propose that pathological genetic changes in excitatory cells ultimately initiates pathological changes in other cell types contributing to the multiple cellular pathologies observed in SCZ. We will: 1. Identify cell type-specific gene regulatory networks involved in SCZ (SCZ-GRNs) in prefrontal cortical excitatory cells by analysis of four distinct SCZ mouse models. 2. Confirm putative SCZ-GRNs in patient material using in situ transcriptomics on postmortem brains and connect to clinical features via collaboration with genomic studies in Sweden and Denmark. 3. Functionally investigate the effects of perturbing excitatory cell SCZ-GRNs on other cell types. Single-cell RNA-seq, providing insights into the molecular properties of individual cells, and modern molecular tools for perturbing transcription in a cell type-specific way opens up for new knowledge of mechanisms underlying SCZ pathology. My work will identify causal relationships that can be exploited for the development of strategies for personalized treatment.

2 064 414 €

Start date: 2019-04-01, End date: 2024-03-31

The main and most important feature of vaccines is the induction of an immunological memory response, which is key to providing long-term protection against pathogens. The current strategies for potent antibacterial and antiviral vaccines employ conjugation of pathogen specific entities onto carrier proteins, and are limited to formulations that suffer from low stability and short shelf-lives, and are thus not viable in developing countries. Strategies for the development of new vaccinations against endogenous diseases like cancer further remain an unmet challenge, since current methodologies suffer from a lack of a modular and tailored vaccine-specific functionalisation. I therefore propose a radically new design approach in the development of fully synthetic molecular vaccines. My team will synthesise carbohydrate and glycopeptide appended epitopes that are grafted onto supramolecular building blocks. These units can be individually designed to attach disease specific antigens and immunostimulants. Due to their self-assembling properties into nanoscaled pathogen mimetic particles, they serve as a supramolecular subunit vaccine toolbox. By developing a universal supramolecular polymer platform, we will construct multipotent vaccines from glycan-decorated peptides, that combine the activity of protein conjugates with the facile handling, precise composition and increased stability of traditional small molecule pharmaceutical compounds. SUPRAVACC will pioneer the design of minimalistic and broadly applicable vaccines, and will evaluate the supramolecular engineering approach for immunisations against antibacterial diseases, as well as for applications as antitumour vaccine candidates. The fundamental insights gained will drive a paradigm shift in the design and preparation of vaccine candidates in academic and industrial research laboratories.

2 000 000 €

Start date: 2019-04-01, End date: 2024-03-31

The proceeding inexorable digitalisation of modern economics and society creates a steadily increasing demand on smart devices in the context of the industrial internet and the internet of things. To meet future requirements, organic electronics is a disruptive technology featuring low-cost, robust, lightweight, flexible and affordable devices based on organic small molecules and polymers. In contrast to the boosting development of linear conjugated polymers and their applications in organic electronics, the successive increase of dimensionality by connecting multiple strands towards two-dimensional (2D) conjugated polymers remains largely unexplored. In this project, we will develop unprecedented thiophene-based double- and triple-strand conjugated polymers to 2D conjugated polymers (T2DCPs) for organic electronics with tailorable electronic band gap at the molecular level for superior performance in terms of charge carrier mobility, and defect tolerance enabled by the increased dimensionality. In this respect, we aim to establish versatile but also reliable solution-based synthesis strategies (one-pot solvothermal, two-step metal-templating reaction and interfacial soft-templating route) employing thiophene monomers rendering T2DCPs with entirely C=C/Ar-Ar backbone. We will further establish ground-breaking one-pot synthesis of donor-acceptor type T2DCPs featuring lower band gap and unique charge transport behavior. By employing designed thiophene-based monomers and linkage topologies, we will accomplish optical and energy gap engineering, control of the molecular weight (or crystalline domain size), and conjugation channel densities. The consequence is that we will explore the key functions of this intriguing class of semiconducting polymers. As the key achievements, we expect to establish a novel solution-based chemistry, delineation of reliable structure-property relationships and superior device performance of T2DCPs for organic field effect transistors.

2 000 000 €

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

Almost 100 years ago, Warburg described a metabolic change in energy flux that occurs during carcinogenesis. Since then, multiple studies have demonstrated how anabolic synthesis of macromolecules can be altered to support cancer cell progression. Yet, the potential effect of altered catabolic degradation of macromolecules on tumour carcinogenesis has been much less studied. The urea cycle (UC) is the main catabolic pathway by which mammals excrete waste nitrogen. Although the complete UC pathway is liver-specific, most tissues express different combinations of UC enzymes according to the cellular needs. Surprisingly, we find that changes in expression of UC components causing UC dysregulation, (UCD) is a global phenomenon in cancer, metabolically augmenting net nitrogen usage for the synthesis of macromolecules by reducing nitrogen waste. This metabolic alteration is associated with poor patient prognosis. Thus, we hypothesise that UCD provides a major metabolic advantage to multiple aspects of carcinogenesis and as such, leads to specific, identifiable genomic and biochemical signatures, with implications for cancer diagnosis and therapy. To pursue our hypothesis, we will incorporate state-of-the-art comparative genomic, peptidomic, metabolomic, and molecular approaches to explore this scientific “blind spot” of nitrogen metabolism in carcinogenesis. We will investigate how UCD causally affects carcinogenesis, by characterising tumour-specific functions of UC enzymes (Aim I), correlating tumour phenotypes with systemic biomarkers (Aim II), and testing the treatment efficacy of drug combinations targeting UCD in cancers (Aim III). Our proposal, strengthened by my training as a physician scientist, harbours considerable potential for translational diagnostic and therapeutic utility of our findings, enabling us to i) identify new diagnostic biomarkers for monitoring cancer initiation and progression and ii) predict and enhance the therapeutic response.

2 000 000 €

Start date: 2019-05-01, End date: 2024-04-30