ERC FUNDED PROJECTS

"This proposal addresses major questions in particle physics that are at the forefront of experimental and theoretical physics research today. The results offered would have far-reaching implications in other fields such as cosmology and could help answer some of the big questions such as why the universe contains so much more matter than antimatter. The research objectives of this proposal are to (i) make world-leading tests of CPT symmetry and (ii) discover the neutrino mass hierarchy and search for indications of leptonic CP violation. The NOvA long-baseline neutrino oscillation experiment will use a novel ""totally active scintillator design"" for the detector technology and will be exposed to the world's highest power neutrino beam. Building on the first direct observation of muon antineutrino disappearance (that was made by a group founded and led by the PI at the MINOS experiment), tests of CPT symmetry will be performed by looking for differences in the mass squared splittings and mixing angles between neutrinos and antineutrinos. The potential to discover the mass hierarchy is unique to NOvA on the timescale of this proposal due to the long 810 km baseline and the well measured beam of neutrinos and antineutrinos. This proposal addresses several key challenges in a long-baseline neutrino oscillation experiment with the following tasks: (i) development of a new approach to event energy reconstruction that is expected to have widespread applicability for future neutrino experiments; (ii) undertaking a comprehensive calibration project, exploiting a novel technique developed by the PI, that will be essential to achieving the physics goals; (iii) development of a sophisticated statistical analyses. The results promised in this proposal surpass the sensitivity to antineutrino oscillation parameters of current 1st generation experiments by at least an order of magnitude, offering wide scope for profound discoveries with implications across disciplines."

1 415 848 €

Start date: 2012-10-01, End date: 2018-09-30

Plant and animal organs display a remarkable diversity of shapes. A major challenge in developmental and evolutionary biology is to understand how this diversity of forms is generated. Recent advances in imaging, computational modelling and genomics now make it possible to address this challenge effectively for the first time. Leaf development is a particularly tractable system because of its accessibility to imaging and preservation of connectivity during growth. Leaves also display remarkable diversity in shape and form, with perhaps the most complex form being the pitcher-shaped (epiascidiate) leaves of carnivorous plants. This form has evolved four times independently, raising the question of whether its seeming complexity may have arisen through simple modulations in underlying morphogenetic mechanisms. To test this hypothesis, I aim to develop a model system for carnivorous plants based on Utricularia gibba (humped bladderwort), which has the advantage of having one of the smallest genomes known in plants (~2/3 the size of the Arabidopsis genome) and small transparent pitcher-shaped leaves amenable to imaging. I will use this system to define the morphogenetic events underlying the formation of pitcher-shaped leaves and their molecular genetic control. I will also develop and apply computational modelling to explore hypotheses that may account for the development of U. gibba bladders and further test these hypotheses experimentally. In addition, I will investigate the relationship between U. gibba bladder development and species with simpler leaf shapes, such as Arabidopsis, or species where the epiascidiate form has evolved independently. Taken together, these studies should show how developmental rules elucidated in current model systems might be extended and built upon to account for the diversity and complexity of tissue forms, integrating evo-devo approaches with a mechanistic understanding of morphogenesis.

2 499 997 €

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

The widespread use of electronic devices, artificial light and rise of the 24-hour economy means that more individuals experience disruption of their chronotype, which is the natural circadian rhythm that regulates sleep and activity levels. The natural and medical sciences focus on the natural environment (e.g., light exposure), genetics, biology and health consequences, whereas the social sciences have largely explored the socio-environment (e.g., working regulations) and psychological and familial consequences of nonstandard work schedules. For the first time CHRONO bridges these disparate disciplines to ask: What is the role of biology, the natural and socio-environment and their interaction on predicting and understanding resilience to chronotype disruption and how does this in turn impact an individual’s health (sleep, cancer, obesity, digestive problems) and family (partnership, children) outcomes? I propose to: (1) develop a multifactor interdisciplinary theoretical model; (2) disrupt data collection by crowdsourcing a sociogenomic dataset with novel measures; (3) discover and validate with informed machine learning innovative measures of chronotype (molecular genetic, accelerometer, microbiome, patient-record, self-reported) and the natural and socio-environment; (4) ask fundamentally new substantive questions to determine how chronotype disruption influences health and family outcomes and, via Biology x Environment interaction (BxE), whether this is moderated by the natural or socio-environment; and, (5) develop new statistical models and methods to cope with contentious issues, answer longitudinal questions and engage in novel quasi-experiments (e.g., policy and life course changes) to transcend description to identify endogenous factors and causal mechanisms. Interdisciplinary in the truest sense, CHRONO will overturn long-held substantive findings of the causes and consequences of chronotype disruption.

2 499 811 €

Start date: 2019-11-01, End date: 2024-10-31

Colorectal cancer (CRC) is one of the most common cancers of the western world. The underlying initiating mutation for the majority of CRC is within the Adenomatous Polyposis Coli (Apc) gene. The APC protein performs an important role in controlling the levels of Wnt signalling by targeting beta-catenin for degradation. Loss of the APC protein leads to the activation of Wnt signaling target genes such as c-Myc which is required for phenotypes causes by Apc loss. However, despite the clear importance of APC loss and deregulated Wnt signalling, additional events are required for the development of CRC such as KRAS and P53 mutations.The impact of these changes on the development of CRC and response to therapy is not well understood. Furthermore, identification and testing of potential novel targets and therapies is hampered by lack of a preclinical model that faithfully recapitulates the course of the human disease. This proposal has two aims: 1. Assess the impact of cooperating mutations with Apc and assess how they alter sensitivities of Apc deficient cells. 2. Develop mouse models of invasive and metastatic colorectal cancer that recapitulate the human disease. We will use ‘state of the art’ methodologies to identify the changes in signaling output conferred by these cooperating mutations. Genetic mouse models of invasive and metastatic colorectal cancers will be generated through the acquisition of additional mutations and genomic instability. These studies will produce predictions on therapeutic combinations that will be tested in mouse models in vitro and in vivo that may identify new treatment regimens for patients with late stage CRC.

1 499 045 €

Start date: 2012-11-01, End date: 2017-10-31

Organisms and cells face a myriad of environmental changes with periods of nutrient surplus and shortage. It is therefore not surprising that in all kingdoms of life, cells have evolved the means to store energy and thereby minimize the effects of environmental fluctuations. While the capability for energy storage has obvious advantages, deregulated energy accumulation can also be detrimental and is the hallmark of many diseases such as obesity. In most cells energy is stored as neutral lipids in a dedicated cellular compartment, the lipid droplets (LDs). LDs are found in virtually every eukaryotic cell and play a central role in cellular lipid and energy metabolism. Despite their ubiquitous presence and importance, the physiology of LDs is poorly understood. LDs are composed of a single lipid layer and therefore distinct from all other cellular compartments. How do LDs originate at the endoplasmic reticulum (ER) and what is the machinery involved? How is the size, number and the storage capacity of the LDs regulated? How are specific proteins and lipids targeted to LDs? Addressing these questions is fundamental for understanding the “life cycle” of LDs and for a global picture of the cellular energy homeostasis. The main goal of this proposal is to reveal the molecular mechanisms controlling neutral lipid dynamics and their storage in LDs. We will focus specifically on the role of the endoplasmic reticulum in the biogenesis of LDs. First, we will identify the ER protein complexes required for LD formation and regulation. Second, we will develop an assay to dissect the targeting of proteins to LDs. Finally, we will develop a cell-free system that recapitulates the biogenesis of LDs in vitro. Altogether, our strategy constitutes a systematic, in-depth analysis of LD dynamics and will lead to significant insight on the mechanisms of cellular energy storage. Our findings will likely offer a better understanding of human pathologies such as obesity and lipodistrophies

1 475 282 €

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

A typical problem of Extremal Combinatorics is to maximise or minimise a certain parameter given some combinatorial restrictions. This area experienced a remarkable growth in the last few decades, having a wide range of applications that include results in number theory, algebra, geometry, logic, information theory, and theoretical computer science. There are also many practical fields that were greatly influenced by ideas from Extremal Combinatorics such as, for example, analysis of large networks, ranking of web-pages, or shotgun cloning of DNA fragments. The Principal Investigator (PI for short) will work on a number of extremal problems, with the main directions being the Tur\'an function (maximising the size of a hypergraph without some fixed forbidden subgraphs), the Rademacher-Tur\'an problem (minimising the density of F-subgraphs given the edge density), and Ramsey numbers (quantitative bounds on the maximum size of a monochromatic substructure that exists for every colouring). These are fundamental and general questions that go back at least as far as the 1940s but remain wide open despite decades of active attempts. During attacks on these notoriously difficult problems, mathematicians developed a number of powerful general methods. PI will work on extending and sharpening these techniques as well as on finding ways of applying the recently introduced concepts of (hyper)graph limits and flag algebras to concrete extremal problems. Since these concepts deal with some approximation to the studied problem, one important aspect of the project is to develop methods for obtaining exact results from asymptotic calculations (for example, via the stability approach). The support by means of a 5-year research grant will enable PI to consolidate his research and build a group in Extremal Combinatorics.

1 129 919 €

Start date: 2012-10-01, End date: 2018-07-31

The subject of this proposal lies at the crossroads of analysis, additive combinatorics, number theory and fractal geometry exploring equidistribution phenomena for random walks on groups and group actions and regularity properties of self-similar, self-affine and Furstenberg boundary measures and other kinds of stationary measures. Many of the problems I will study in this project are deeply linked with problems in number theory, such as bounds for the separation between algebraic numbers, Lehmer's conjecture and irreducibility of polynomials. The central aim of the project is to gain insight into and eventually resolve problems in several main directions including the following. I will address the main challenges that remain in our understanding of the spectral gap of averaging operators on finite groups and Lie groups and I will study the applications of such estimates. I will build on the dramatic recent progress on a problem of Erdos from 1939 regarding Bernoulli convolutions. I will also investigate other families of fractal measures. I will examine the arithmetic properties (such as irreducibility and their Galois groups) of generic polynomials with bounded coefficients and in other related families of polynomials. While these lines of research may seem unrelated, both the problems and the methods I propose to study them are deeply connected.

1 334 109 €

Start date: 2018-10-01, End date: 2023-09-30

Spiral cleavage is a highly stereotypical early embryonic program, and the ancestral, defining feature to Spiralia, a major phylogenetic clade including almost half of the animal phyla. Remarkably, spiral-cleaving embryos specify homologous cell fates (e.g. the progenitor cell of posterodorsal structures) conditionally –via cell interactions– or autonomously –via segregation of maternal inputs. This variation occurs naturally, even between closely related species, and has been related to the precocious formation of adult characters (adultation) in larvae of autonomous spiral-cleaving species. How spiralian lineages repeatedly shifted between these two cell fate specification modes is largely unexplored, because the mechanisms controlling spiral cleavage are still poorly characterized. This project tests the hypothesis that maternal chromatin and transcriptional regulators differentially incorporated in oocytes with autonomous spiral cleavage explain the evolution of this mode of cell fate specification. Through a comparative and phylogenetic-guided approach, we will combine bioinformatics, live imaging, and molecular and experimental techniques to: (i) Comprehensively identify differentially supplied maternal factors among spiral cleaving oocytes with distinct cell fate specification modes using comparative RNA-seq and proteomics; (ii) Uncover the developmental mechanisms driving conditional spiral cleavage, which is the ancestral embryonic mode; and (iii) Investigate how maternal chromatin and transcriptional regulators define early cell fates, and whether these factors account for the repeated evolution of autonomous specification modes. Our results will fill a large gap of knowledge in our understanding of spiral cleavage and its evolution. In a broader context, this project will deliver fundamental insights into two core questions in evolutionary developmental biology: how early embryonic programs evolve, and how they contribute to phenotypic change.

1 500 000 €

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

"This proposal sits at the interface of analytic number theory and selected topics, viewed through the prism of Diophantine equations defining higher-dimensional algebraic varieties. A core part of the proposal involves using analytic methods (such as complex analysis, Fourier analysis and additive combinatorics) to tackle a range of problems about Diophantine equations. These include such basic questions as precisely when families of equations admit integer or rational solutions and, furthermore, how ``dense'' these solutions are when they exist. In the reverse direction, a significant component of the proposal is dedicated to established problems in number theory (such as stable cohomology of moduli spaces and uniform spectral gaps for arithmetic lattices) which can be tackled via the successful analysis of intermediary Diophantine equations."

801 187 €

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