ERC FUNDED PROJECTS

The world has a significant medical challenge in repairing injured or diseased joints. Joint degeneration and its related pain is a major socio-economic burden that will increase over the next decade and is currently addressed by implanting a metal prosthesis. For the long term, the ideal solution to joint injury is to successfully regenerate rather than replace the damaged cartilage with synthetic implants. Recent advances in key technologies are now bringing this “holy grail” within reach; regenerative approaches, based on cell therapy, are already clinically available albeit only for smaller focal cartilage defects. One of these key technologies is three-dimensional (3D) bio-printing, which provides a greatly controlled placement and organization of living constructs through the layer-by-layer deposition of materials and cells. These tissue constructs can be applied as tissue models for research and screening. However, the lack of biomechanical properties of these tissue constructs has hampered their application to the regeneration of damaged, degenerated or diseased tissue. Having established a cartilage-focussed research laboratory in the University Medical Center Utrecht, I have addressed this biomechanical limitation of hydrogels through the use of hydrogel composites. Specifically, I have pioneered a 3D bio-printing technology that combines accurately printed small diameter thermoplast filaments with cell invasive hydrogels to form strong fibre-reinforced constructs. This, in combination with bioreactor technology, is the key to the generation of larger, complex tissue constructs with cartilage-like biomechanical resilience. With 3D-JOINT I will use my in-depth bio-printing and bioreactor knowledge and experience to develop a multi-phasic 3D-printed biological replacement of the joint.

1 998 871 €

Start date: 2015-07-01, End date: 2020-06-30

Chronic lung diseases are increasing in prevalence with over 65 million patients worldwide. Lung transplantation remains the only potential option at end-stage disease. Around 4000 patients receive lung transplants annually with more awaiting transplantation, including 1000 patients in Europe. New options to increase available tissue for lung transplantation are desperately needed. An exciting new research area focuses on generating lung tissue ex vivo using bioengineering approaches. Scaffolds can be generated from synthetic or biologically-derived (acellular) materials, seeded with cells and grown in a bioreactor prior to transplantation. Ideally, scaffolds would be seeded with cells derived from the transplant recipient, thus obviating the need for long-term immunosuppression. However, functional regeneration has yet to be achieved. New advances in 3D printing and 3D bioprinting (when cells are printed) indicate that this once thought of science-fiction concept might finally be mature enough for complex tissues, including lung. 3D bioprinting addresses a number of concerns identified in previous approaches, such as a) patient heterogeneity in acellular human scaffolds, b) anatomical differences in xenogeneic sources, c) lack of biological cues on synthetic materials and d) difficulty in manufacturing the complex lung architecture. 3D bioprinting could be a reproducible, scalable, and controllable approach for generating functional lung tissue. The aim of this proposal is to use custom 3D bioprinters to generate constructs mimicking lung tissue using an innovative approach combining primary cells, the engineering reproducibility of synthetic materials, and the biologically conductive properties of acellular lung (hybrid). We will 3D bioprint hybrid murine and human lung tissue models and test gas exchange, angiogenesis and in vivo immune responses. This proposal will be a critical first step in demonstrating feasibility of 3D bioprinting lung tissue.

1 499 975 €

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

Large protein complexes carry out some of the most complex functions in biology. Such structures are often assembled spontaneously from individual components through the process of self-assembly. If self-assembled protein complexes could be engineered from first principle it would enable a wide range of applications in biomedicine, nanotechnology and materials science. Recently, approaches to rationally design proteins to self-assembly into predefined structures have emerged. The highlight of this work is the design of protein cages that may be engineered into protein containers. However, current approaches for self-assembly design does not result in the assemblies with the required structural complexity to encode many of the sophisticated functions found in nature. To move forward, we have to learn how to engineer protein subunits with more than one designed interface that can assemble into tightly interacting complexes. In this proposal we propose a new protein design paradigm, shape directed protein design, in order to address shortcomings of the current methodology. The proposed method combines geometric shape matching and computational protein design. Using this approach we will de novo design assemblies with a wide variety of structural states, including protein complexes with cyclic and dihedral symmetry as well as icosahedral protein capsids built from novel protein building blocks. To enable these two design challenges we also develop a high-throughput assay to measure assembly stability in vivo that builds on a three-color fluorescent assay. This method will not only facilitate the screening of orders of magnitude more design constructs, but also enable the application of directed evolution to experimentally improve stable and assembly properties of designed containers as well as other designed assemblies.

2 325 292 €

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

Mucins are a family of high-molecular-weight glycoproteins and a major macromolecular constituent in slimy mucus gels that are covering the surface of internal biological tissues. A primary role of mucus gels in biological systems is known to be the protection and lubrication of underlying epithelial cell surfaces. This is intuitively well appreciated by both science community and the public, and yet detailed lubrication properties of mucins and mucus gels have remained largely unexplored to date. Detailed and systematic understanding of the lubrication mechanism of mucus gels is significant from many angles; firstly, lubricity of mucus gels is closely related with fundamental functions of various human organs, such as eye blinking, mastication in oral cavity, swallowing through esophagus, digestion in stomach, breathing through air way and respiratory organs, and thus often indicates the health state of those organs. Furthermore, for the application of various tissue-contacting devices or personal care products, e.g. catheters, endoscopes, and contact lenses, mucus gel layer is the first counter surface that comes into the mechanical and tribological contacts with them. Finally, remarkable lubricating performance by mucins and mucus gels in biological systems may provide many useful and possibly innovative hints in utilizing water as base lubricant for man-made engineering systems. This project thus proposes to carry out a 5 year research program focusing on exploring the lubricity of mucins and mucus gels by combining a broad range of experimental approaches in biology and tribology.

1 432 920 €

Start date: 2011-04-01, End date: 2016-03-31

Developing new therapeutic strategies for heart regeneration is a major goal for cardiac biology and medicine. While cardiomyocytes can be generated from human pluripotent stem (hPSC) cells in vitro, it has proven difficult to use these cells to generate a large scale, mature human heart ventricular muscle graft on the injured heart in vivo. The central objective of this proposal is to optimize the generation of a large-scale pure, fully functional human ventricular muscle patch in vivo through the self-assembly of purified human ventricular progenitors and the localized expression of defined paracrine factors that drive their expansion, differentiation, vascularization, matrix formation, and maturation. Recently, we have found that purified hPSC-derived ventricular progenitors (HVPs) can self-assemble in vivo on the epicardial surface into a 3D vascularized, and functional ventricular patch with its own extracellular matrix via a cell autonomous pathway. A two-step protocol and FACS purification of HVP receptors can generate billions of pure HVPs- The current proposal will lead to the identification of defined paracrine pathways to enhance the survival, grafting/implantation, expansion, differentiation, matrix formation, vascularization and maturation of the graft in vivo. We will captalize on our unique HVP system and our novel modRNA technology to deliver therapeutic strategies by using the in vivo human ventricular muscle to model in vivo arrhythmogenic cardiomyopathy, and optimize the ability of the graft to compensate for the massive loss of functional muscle during ischemic cardiomyopathy and post-myocardial infarction. The studies will lead to new in vivo chimeric models of human cardiac disease and an experimental paradigm to optimize organ-on-organ cardiac tissue engineers of an in vivo, functional mature ventricular patch for cardiomyopathy

2 149 228 €

Start date: 2017-12-01, End date: 2022-11-30

In todays advanced technological world, we can track the exact movement of individuals, analyse their genetic makeup and predict predisposition to certain diseases. However, we are unable to accurately assess an individual’s dietary intake. This is without a doubt one of the main stumbling blocks in assessing the link between diet and disease/health. The present proposal (A-DIET) will address this issue with the overarching objective to develop novel strategies for assessment of dietary intake. Using approaches to (1) identify biomarkers of specific foods (2) classify people into dietary patterns (nutritypes) and (3) develop a tool for integration of dietary and biomarker data, A-DIET has the potential to dramatically enhance our ability to accurately assess dietary intake. The ultimate output from A-DIET will be a dietary assessment tool which can be used to obtain an accurate assessment of dietary intake by combining dietary and biomarker data which in turn will allow investigations into relationships between diet, health and disease. New biomarkers of specific foods will be identified and validated using intervention studies and metabolomic analyses. Methods will be developed to classify individuals into dietary patterns based on biomarker/metabolomic profiles thus demonstrating the novel concept of nutritypes. Strategies for integration of dietary and biomarker data will be developed and translated into a tool that will be made available to the wider scientific community. Advances made in A-DIET will enable nutrition epidemiologist’s to properly examine the relationship between diet and disease and develop clear public health messages with regard to diet and health. Additionally results from A-DIET will allow researchers to accurately assess people’s diet and implement health promotion strategies and enable dieticians in a clinical environment to assess compliance to therapeutic diets such as adherence to a high fibre diet or a gluten free diet.

1 995 548 €

Start date: 2015-08-01, End date: 2020-07-31

Aerosols (i.e. tiny particles suspended in the air) are regularly transported in huge amounts over long distances impacting air quality, health, weather and climate thousands of kilometers downwind of the source. Aerosols affect the atmospheric radiation budget through scattering and absorption of solar radiation and through their role as cloud/ice nuclei. In particular, light absorption by aerosol particles such as mineral dust and black carbon (BC; thought to be the second strongest contribution to current global warming after CO2) is of fundamental importance from a climate perspective because the presence of absorbing particles (1) contributes to solar radiative forcing, (2) heats absorbing aerosol layers, (3) can evaporate clouds and (4) change atmospheric dynamics. Considering this prominent role of aerosols, vertically-resolved in-situ data on absorbing aerosols are surprisingly scarce and aerosol-dynamic interactions are poorly understood in general. This is, as recognized in the last IPCC report, a serious barrier for taking the accuracy of climate models and predictions to the next level. To overcome this barrier, I propose to investigate aging, lifetime and dynamics of absorbing aerosol layers with a holistic end-to-end approach including laboratory studies, airborne field experiments and numerical model simulations. Building on the internationally recognized results of my aerosol research group and my long-term experience with airborne aerosol measurements, the time seems ripe to systematically bridge the gap between in-situ measurements of aerosol microphysical and optical properties and the assessment of dynamical interactions of absorbing particles with aerosol layer lifetime through model simulations. The outcomes of this project will provide fundamental new understanding of absorbing aerosol layers in the climate system and important information for addressing the benefits of BC emission controls for mitigating climate change.

1 987 980 €

Start date: 2015-10-01, End date: 2020-09-30

Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations: - First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37); - Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells (Turk et al.,Cancer Res, 2009. 69(21)); - Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15); - Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204). I propose a comprehensive series of studies that will address thefollowing critical questions: - First, what is the scope of MDR-selective compounds? - Second, what is their mechanism of action? - Third, what is the optimal therapeutic modality? Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.

1 499 640 €

Start date: 2012-01-01, End date: 2016-12-31

Global change involves a large number of complex interactions between various earth system processes. In the atmosphere, one component of the earth system, there are crucial feedbacks between physical, chemical and biological processes. Thus many of the drivers of climate change depend on chemical processes in the atmosphere including, in addition to ozone and water vapour, methane, nitrous oxide, the halocarbons as well as a range of inorganic and organic aerosols. The link between chemistry and climate is two-way and changes in climate can influence atmospheric chemistry processes in a variety of ways. Previous studies have looked at these interactions in isolation but the time is now right for more comprehensive studies. The crucial contribution that will be made here is in improving our understanding of the processes within this complex system. Process understanding has been the hallmark of my previous work. The earth system scope here will be ambitiously wide but with a similar drive to understand fundamental processes. The ambitious programme of research is built around four interrelated questions using new state-of-the-art modelling tools: How will the composition of the stratosphere change in the future, given changes in the concentrations of ozone depleting substances and greenhouse gases? How will these changes in the stratosphere affect tropospheric composition and climate? How will the composition of the troposphere change in the future, given changes in the emissions of ozone precursors and greenhouse gases? How will these changes in the troposphere affect the troposphere-stratosphere climate system? ACCI will break new ground in bringing all of these questions into a single modelling and diagnostic framework, enabling interrelated questions to be answered which should radically improve our overall projections for global change.

2 496 926 €

Start date: 2011-05-01, End date: 2017-04-30

Rapid changes in ocean circulation and climate have been observed in marine sediment and ice cores, notably over the last 60 thousand years (ky), highlighting the non-linear character of the climate system and underlining the possibility of rapid climate shifts in response to anthropogenic greenhouse gas forcing. To date, these rapid changes in climate and ocean circulation are still not fully explained. Two main obstacles prevent going beyond the current state of knowledge: - Paleoclimatic proxy data are by essence only indirect indicators of the climatic variables, and thus can not be directly compared with model outputs; - A 4-D (latitude, longitude, water depth, time) reconstruction of Atlantic water masses over the past 40 ky is lacking: previous studies have generated isolated records with disparate timescales which do not allow the causes of circulation changes to be identified. Overcoming these two major limitations will lead to major breakthroughs in climate research. Concretely, I will create the first database of Atlantic deep-sea records over the last 40 ky, and extract full climatic information from these records through an innovative model-data integration scheme using an isotopic proxy forward modeling approach. The novelty and exceptional potential of this scheme is twofold: (i) it avoids hypotheses on proxy interpretation and hence suppresses or strongly reduces the errors of interpretation of paleoclimatic records; (ii) it produces states of the climate system that best explain the observations over the last 40 ky, while being consistent with the model physics. Expected results include: • The elucidation of the mechanisms explaining rapid changes in ocean circulation and climate over the last 40 ky, • Improved climate model physics and parameterizations, • The first projections of future climate changes obtained with a model able to reproduce the highly non linear behavior of the climate system observed over the last 40 ky.

3 000 000 €

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

Demand for biofuels and other biologically derived commodities is growing worldwide as efforts increase to reduce reliance on fossil fuels and to limit climate change. Most commercial approaches rely on fermentations of organic matter with its inherent problems in producing CO2 and being in conflict with the food supply of humans. These problems are avoided if CO2 can be used as feedstock. Autotrophic organisms can fix CO2 by producing chemicals that are used as building blocks for the synthesis of cellular components (Biomass). Acetate-forming bacteria (acetogens) do neither require light nor oxygen for this and they can be used in bioreactors to reduce CO2 with hydrogen gas, carbon monoxide or an organic substrate. Gas fermentation using these bacteria has already been realized on an industrial level in two pre-commercial 100,000 gal/yr demonstration facilities to produce fuel ethanol from abundant waste gas resources (by LanzaTech). Acetogens can metabolise a wide variety of substrates that could be used for the production of biocommodities. However, their broad use to produce biofuels and platform chemicals from substrates other than gases or together with gases is hampered by our very limited knowledge about their metabolism and ability to use different substrates simultaneously. Nearly nothing is known about regulatory processes involved in substrate utilization or product formation but this is an absolute requirement for metabolic engineering approaches. The aim of this project is to provide this basic knowledge about metabolic routes in the acetogenic model strain Acetobacterium woodii and their regulation. We will unravel the function of “organelles” found in this bacterium and explore their potential as bio-nanoreactors for the production of biocommodities and pave the road for the industrial use of A. woodii in energy (hydrogen) storage. Thus, this project creates cutting-edge opportunities for the development of biosustainable technologies in Europe.

2 497 140 €

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

Increasing crop yield to feed the world is a grand challenge of the 21st century but it is hampered by diseases caused by filamentous plant pathogens. The arms race between pathogen and plant demands constant adjustment of crop germplasm to tackle emerging pathogen races with new virulence features. To date, most crop disease resistance has relied on specific resistance genes that are effective only against a subset of races. We cannot solely rely on classical resistance genes to keep ahead of the pathogens. There is an urgent need to develop approaches based on knowledge of the pathogen’s Achilles heel: core plant processes that are required for pathogen colonization. Our hypothesis is that disease resistance based on manipulation of host accessibility processes has a higher probability for durability, and is best identified using a broad host-range pathogen. I will employ the filamentous pathogen Phytophthora palmivora to mine plant alleles and unravel host processes providing microbial access in roots and leaves of monocot and dicot plants. In Aim 1 I will utilize plant symbiosis mutants and allelic variation to elucidate general mechanisms of colonization by filamentous microbes. Importantly, allelic variation will be studied in economically relevant barley and wheat to allow immediate translation into breeding programs. In Aim 2 I will perform a comparative study of microbial colonization in monocot and dicot roots and leaves. Transcriptional profiling of pathogen and plant will highlight common and contrasting principles and illustrate the impact of differential plant anatomies. We will challenge our findings by testing beneficial fungi to assess commonalities and differences between mutualist and pathogen colonization. We will use genetics, cell biology and genomics to find suitable resistance alleles highly relevant to crop production and global food security. At the completion of the project, I expect to have a set of genes for resistance breeding.

1 991 054 €

Start date: 2015-09-01, End date: 2021-08-31

Computer models based on known physical laws are our primary tool for predicting climate change. Yet the state-of-the-art models exhibit a disturbingly wide range of predictions of future climate change, especially when examined at the regional scale, which has not decreased as the models have become more comprehensive. The reasons for this are not understood. This represents a basic challenge to our fundamental understanding of climate. The divergence of model projections is presumably related to systematic model errors in the large-scale fluxes of heat, moisture and momentum that control regional aspects of climate. That these errors stubbornly persist in spite of increases in the spatial resolution of the models suggests that they are associated with errors in the representation of unresolved processes, whose effects must be parameterised. Most attention in climate science has hitherto focused on the thermodynamic aspects of climate. Dynamical aspects, which involve the atmospheric circulation, have received much less attention. However regional climate, including persistent climate regimes and extremes, is strongly controlled by atmospheric circulation patterns, which exhibit chaotic variability and whose representation in climate models depends sensitively on parameterised processes. Moreover the dynamical aspects of model projections are much less robust than the thermodynamic ones. There are good reasons to believe that model bias, the divergence of model projections, and chaotic variability are somehow related, although the relationships are not well understood. This calls for studying them together. My proposed research will focus on this problem, addressing these three aspects of the atmospheric circulation response to climate change in parallel: (i) diagnosing the sources of model error; (ii) elucidating the relationship between model error and the spread in model projections; (iii) understanding the physical mechanisms of atmospheric variability.

2 489 151 €

Start date: 2014-03-01, End date: 2020-02-29

The human kind is witnessing an escalation of obesity-related health problems such as cardiovascular diseases and type 2 diabetes. A recent groundbreaking study revealed adiponectin receptors (ADIPOR) as key targets for treating such obesity-related diseases. Indeed, the modulation of this integral membrane protein by small molecules agonists ameliorates diabetes and prolongs lifespan of genetically obese rodent model. Despite these exciting results and the importance of ADIPOR in human physiology, there is a complete lack of knowledge of ADIPOR mechanisms of action and pharmacology. This is mainly due to the challenges associated with the characterization of membrane protein structure and function. To fill this gap of knowledge and based on my extensive experience in membrane protein biology, I propose here to characterize the the proximal signaling pathways associated with ADIPOR activation as well as the molecular and structural mechanisms of ADIPOR activation. We will develop an innovative integrated strategy combining state-of-the-art molecular and structural pharmacology approaches including 1) molecular analyses of ADIPOR network of interaction using resonance energy transfer measurement in living cells and a proteomic analysis and 2) structural analyses of ADIPOR and signaling complexes using biophysics and X-ray crystallography. Our data will have a major impact on drug discovery for treating obesity-related diseases as it will enable the application of structure-based drug design and in silico screening for the molecular control of ADIPOR activity. The proposed high-risk endeavor of obtaining structural data on these atypical membrane signaling complexes is a new direction both for my career and for the field of adiponectin biology; the exceptionally high gain from these studies fully justifies the risks; the feasibility of this project is supported by my recent success in membrane protein pharmacology, biochemistry, biophysics and crystallography.

1 989 518 €

Start date: 2015-07-01, End date: 2020-06-30

This proposal is focused in the areas of chemical medicine and chemical biology with the key drivers being the discovery and development of new materials that have practical functionality and application. The project will enable the fabrication of thousands of three-dimensional “smart-polymers” that will allow: (i). The precise and controlled release of drugs upon the addition of either a small molecule trigger or in response to disease, (ii). The discovery of materials that control and manipulate cells with the identification of scaffolds that provide the necessary biochemical cues for directing cell fate and drive tissue regeneration and (iii). The development of new classes of “smart-polymers” able, in real-time, to sense and report bacterial contamination. The newly discovered materials will find multiple biomedical applications in regenerative medicine and biotechnology ranging from 3D cell culture, bone repair and niche stabilisation to bacterial sensing/removal, while offering a new paradigm in drug delivery with biomarker triggered drug release.

2 310 884 €

Start date: 2014-11-01, End date: 2019-10-31

The project aims to systematically explore an entire field of current forms of theatre, which despite its outstanding cultural and political significance has so far largely been ignored by theatre studies. Over the past two decades, notwithstanding intense competition from television and electronic media, theatre has been able to reassert and even reinforce its relevance in many different parts of the world and in widely diverse cultural fields (politics, business, social work, development aid, health care, and education). This renewed relevance originates not in traditional, experimental, or commercial theatre but rather among the many different types of applied theatre, which set in motion constructive social processes while upholding theatre’s aesthetic claim. Theatre with clear social, political, or economic aims is experiencing an unprecedented boom. The study will analyse this cross-cultural trend against the background of new theories of the aesthetics of performances and rehearsal processes. This theatre studies approach promises precise insights into the aesthetic forms of applied theatre, which constitute the (hitherto barely researched) foundation of its political effects. It will furthermore bring to light the ethical issues of applied theatre: intense aesthetic experiences – often linked with risks when it comes to performances – do not readily fit in with the claim to restore children, youngsters, patients, and other target groups to health, integrity, and self-confidence through theatrical practice. The project aims to show how aesthetic, political, and ethical aspects interact in the practice of applied theatre. Investigations will focus on carefully selected case studies in Africa, Europe, the Middle East, and Latin America, whose comparison will make it possible for the first time to capture the worldwide landscape of applied theatre in its full diversity, but also in its overarching structures and interrelations.

2 285 295 €

Start date: 2012-12-01, End date: 2017-11-30

A half century since it came into existence, the discipline of Film and Screen Studies remains mostly Eurocentric in its historical, theoretical and critical frameworks. Although “world cinema” and “transnational cinema” scholars have attempted to broaden its canon and frameworks, several major problems persist. Films and scholarship by Africans in particular, and by people of colour in general, are frequently marginalised if not altogether excluded. This prevents exciting exchanges that could help to re-envision Film and Screen Studies for the twenty-first century, in an era in which greater access to the technological means of making films, and circulating them on a range of screens, means that dynamic “screen worlds” are developing at a rapid rate. AFRISCREENWORLDS will study these “screen worlds” (in both their textual forms and industrial structures), with a focus on Africa, as a way of centring the most marginalised regional cinema. We will also elaborate comparative studies of global “screen worlds” – and, in particular, “screen worlds” in the Global South – exploring their similarities, differences, and parallel developments. We will respond to the exclusions of Film and Screen Studies not only in scholarly ways – through conferences and publications – but also in creative and activist ways – through drawing on cutting-edge creative research methodologies (such as audiovisual criticism and filmmaking) and through helping to decolonise Film and Screen Studies (through the production of ‘toolkits’ on how to make curricula, syllabi, and teaching more globally representative and inclusive). On a theoretical level, we will make an intervention through considering how the concept of “screen worlds” is better equipped than “world cinema” or “transnational cinema” to explore the complexities of audiovisual narratives, and their production and circulation in our contemporary moment, in diverse contexts throughout the globe.

1 985 578 €

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

This research will create a new theoretical vision of the importance of marriage as an agent of transformation in human sociality. Marriage globally is undergoing profound change, provoking intense debate and anxiety. These concerns refract wider instabilities in political, economic, and familial institutions. They signal the critical role of marriage in bringing together - and separating - intimate, personal, and familial life with wider state institutions. But we have little up to date comparative research or general theory of how marriage changes or the long-term significance of such change. Paradoxically, social scientific and public discourse emphasise the conservative and normative aspects of marriage. This underlines the need for a new theoretical frame that takes account of cultural and historical specificity to grasp the importance of marriage as both vehicle of and engine for transformation. AGATM overturns conventional understandings by viewing marriage as inherently transformative, indeed at the heart of social and cultural change. The research will investigate current transformations of marriage in two distinct senses. First, it will undertake an ethnographic investigation of new forms of marriage in selected sites in Europe, N. America, Asia, and Africa. Second, it will subject ‘marriage’ to a rigorous theoretical critique that will denaturalise marriage and reintegrate it into the new anthropology of kinship. Research on five complementary and contrastive sub-projects examining emerging forms of marriage in different locations will be structured through the themes of care, property, and ritual forms. The overarching analytic of temporality will frame the theoretical vision of the research and connect the themes. The resulting six monographs, journal articles, and exhibition will together revitalise the study of kinship by placing the moral, practical, political, and imaginative significance of marriage over time at its centre.

2 297 584 €

Start date: 2017-01-01, End date: 2021-12-31

Plants typically release large quantities of volatiles in response to attack by herbivores or pathogens. I may claim to have contributed to various breakthroughs in this research field, including the discovery that the volatile blends induced by different attackers are astonishingly specific, resulting in characteristic, readily distinguishable odour blends. Using maize as our model plant, I wish to take several leaps forward in our understanding of this signal specificity and use this knowledge to develop sensors for the real-time detection of crop pests and diseases. For this, three interconnected work-packages will aim to: • Develop chemical analytical techniques and statistical models to decipher the odorous vocabulary of plants, and to create a complete inventory of “odour-prints” for a wide range of herbivore-plant and pathogen-plant combinations, including simultaneous infestations. • Develop and optimize nano-mechanical sensors for the detection of specific plant volatile mixtures. For this, we will initially adapt a prototype sensor that has been successfully developed for the detection of cancer-related volatiles in human breath. • Genetically manipulate maize plants to release a unique blend of root-produced volatiles upon herbivory. For this, we will engineer gene cassettes that combine recently identified P450 (CYP) genes from poplar with inducible, root-specific promoters from maize. This will result in maize plants that, in response to pest attack, release easy-to-detect aldoximes and nitriles from their roots. In short, by investigating and manipulating the specificity of inducible odour blends we will generate the necessary knowhow to develop a novel odour-detection device. The envisioned sensor technology will permit real-time monitoring of the pests and enable farmers to apply crop protection treatments at the right time and in the right place.

2 498 086 €

Start date: 2018-09-01, End date: 2023-08-31

The scientific motivation of this project is the significant presence of organic compounds at the surface of the ocean. They form the link between ocean biogeochemistry through the physico-chemical processes near the water-air interface with primary and secondary aerosol formation and evolution in the air aloft and finally to the climate impact of marine boundary layer aerosols. However, their photochemistry and photosensitizer properties have only been suggested and discussed but never fully addressed because they were beyond reach. This project suggests going significantly beyond this matter of fact by a combination of innovative tools and the development of new ideas. This project is therefore devoted to new laboratory investigations of processes occurring at the air sea interface to predict emission, formation and evolution of halogenated radicals and aerosols from this vast interface between oceans and atmosphere. It progresses from fundamental laboratory measurements, marine science, surface chemistry, photochemistry … and is therefore interdisciplinary in nature. It will lead to the development of innovative techniques for characterising chemical processing at the air sea interface (e.g., a multiphase atmospheric simulation chamber, a time-resolved fluorescence technique for characterising chemical processing at the air-sea interface). It will allow the assessment of new emerging ideas such as a quantitative description of the importance of photosensitized reactions in the visible at the air/sea interface as a major source of halogenated radicals and aerosols in the marine environment. This new understanding will impact on our ability to describe atmospheric chemistry in the marine environment which has strong impact on the urban air quality of coastal regions (which by the way represent highly populated regions ) but also on climate change by providing new input for global climate models.

2 366 276 €

Start date: 2012-04-01, End date: 2017-03-31

The epidemiology of alcohol use and related health consequences plays a vital role by monitoring populations’ alcohol consumption patterns and problems associated with drinking. Such studies seek to explain mechanisms linking consumption to harm and ultimately to reduce the health burden. Research needs to consider changes in drinking behaviour over the life-course. The current evidence base lacks the consideration of the complexity of lifetime consumption patterns, the predictors of change and subsequent health risks. Aims of the study 1. To describe age-related trajectories of drinking in different settings and to determine the extent to which individual and social contextual factors, including socioeconomic position, social networks and life events influence drinking pattern trajectories. 2. To estimate the impact of drinking trajectories on physical functioning and disease and to disentangle the exposure-outcome associations in terms of a) timing, i.e. health effect of drinking patterns in early, mid and late life; and b) duration, i.e. whether the impact of drinking accumulates over time. 3. To test the bidirectional associations between health and changes in consumption over the life-course in order to estimate the relative importance of these effects and to determine the dominant temporal direction. 4. To explore mechanisms and pathways through which drinking trajectories affect health and functioning in later life and to examine the role played by potential effect modifiers of the association between drinking and poor health. Several large, longitudinal cohort studies from European countries with repeated measures of alcohol consumption will be combined and analysed to address the aims. A new team will be formed consisting of the PI, a Research Associate and two PhD students. Dissemination will be through journals, conferences, and culminating in a one-day workshop for academics, practitioners and policy makers in the alcohol field.

1 032 815 €

Start date: 2013-01-01, End date: 2017-12-31

Zinc finger (ZF) and transcription activator-like effector (TALE) based technologies are been allowing the tailored design of “artificial” DNA-binding proteins targeted to specific and unique DNA genomic sequences. Coupling DNA binding proteins to effectors domains enables the constitution of DNA binding factors for genomic directed transcriptional modulation or targeted genomic editing. We have demonstrated that pairing a ZF DNA binding protein to the transcriptional repressor Kruppel-associated box enables in vivo, the transcriptional repression of one of the most abundantly expressed gene in mammals, the human rhodopsin gene (RHO). We propose to generate RHO DNA binding silencers (“AlleleChoker”), which inactivate RHO either by transcriptional repression or targeted genome modification, irrespectively to wild-type or mutated alleles (mutational-independent approach), and combine RHO endogenous silencing to RHO replacement (silencing-replacement strategy). With this strategy in principle a single bimodal bio-therapeutic will enable the correction of any photoreceptor disease associated with RHO mutation. Adeno-associated viral (AAV) vector-based delivery will be used for photoreceptors gene transfer. Specifically our objectives are: 1) Construction of transcriptional repressors and nucleases for RHO silencing. Characterization and comparison of RHO silencing mediated by transcriptional repressors (ZFR/ TALER) or nucleases (ZFN/ TALEN) to generate genomic directed inactivation by non-homologous end-joining (NHEJ), and refer these results to RNA interference (RNAi) targeted to RHO; 2) RHO silencing in photoreceptors. to determine genome-wide DNA binding specificity of silencers, chromatin modifications and expression profile on human retinal explants; 3) Tuning silencing and replacement. To determine the impact of gene silencing-replacement strategy on disease progression in animal models of autosomal dominant retinitis pigmentosa (adRP) associated to RHO mutations

1 354 840 €

Start date: 2013-02-01, End date: 2018-01-31

"Understanding how organisms regulate size is one of the most fascinating open questions in biology. The aim of the AMAIZE project is to unravel how growth of maize leaves is controlled. Maize leaf development offers great opportunities to study the dynamics of growth regulatory networks, essentially because leaf development is a linear system with cell division at the leaf basis followed by cell expansion and maturation. Furthermore, the growth zone is relatively large allowing easy access of tissues at different positions. Four different perturbations of maize leaf size will be analyzed with cellular resolution: wild-type and plants having larger leaves (as a consequence of GA20OX1 overexpression), both grown under either well-watered or mild drought conditions. Firstly, a 3D cellular map of the growth zone of the fourth leaf will be made. RNA-SEQ of three different tissues (adaxial- and abaxial epidermis; mesophyll) obtained by laser dissection with an interval of 2.5 mm along the growth zone will allow for the analysis of the transcriptome with high resolution. Additionally, the composition of fifty selected growth regulatory protein complexes and DNA targets of transcription factors will be determined with an interval of 5 mm along the growth zone. Computational methods will be used to construct comprehensive integrative maps of the cellular and molecular processes occurring along the growth zone. Finally, selected regulatory nodes of the growth regulatory networks will be further functionally analyzed using a transactivation system in maize. AMAIZE opens up new perspectives for the identification of optimal growth regulatory networks that can be selected for by advanced breeding or for which more robust variants (e.g. reduced susceptibility to drought) can be obtained through genetic engineering. The ability to improve the growth of maize and in analogy other cereals could have a high impact in providing food security"

2 418 429 €

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

Methane, a key greenhouse gas, is cycled by microorganisms via two pathways, aerobically and anaerobically. Research on the marine methane cycle has mainly concentrated on anaerobic processes. Recent biomarker work has provided compelling evidence that aerobic methane oxidation (AMO) can play a more significant role in cycling methane emitted from sediments than previously considered. AMO, however, is not well studied requiring novel proxies that can be applied to the sedimentary record. A group of complex lipids biosynthesised by aerobic methanotrophs known as aminobacteriohopanepolyols represent an ideal target for developing such poxies. Recently BHPs have been identified in a wide range of modern and recent environments including a continuous record from the Congo deep sea fan spanning the last 1.2 million years. In this integrated study, the regulation and expression of BHP will be investigated and calibrated against environmental variables including temperature, pH, salinity and, most importantly, methane concentrations. The work program has three complementary strands. (1) Pure culture and sedimentary microcosm experiments providing an approximation to natural conditions. (2) Calibration of BHP signatures in natural marine settings (e.g. cold seeps, mud volcanoes, pockmarks) against measured methane gradients. (3) Application of this novel approach to the marine sedimentary record to approximate methane fluxes in the past, explore the age and bathymetric limits of this novel molecular proxy, and identify and potentially 14C date palaeo-pockmarks structures. Crucial to the success is also the refinement of the analytical protocols to improve both accuracy and sensitivity, using a more sensitive analytical instrument (triple-quadrupole mass spectrometer).

1 496 392 €

Start date: 2010-11-01, End date: 2016-04-30