ERC FUNDED PROJECTS

Many anti-angiogenic drugs are clinically used in several types of cancer to block angiogenesis, impair tumor growth, progression and dissemination. Nevertheless, clinical trials report emergence of resistance to treatment and a failure in long-lasting effects of these therapies. To date, resistant patients do not currently have any established, proven alternative therapeutic possibility and the medical field is moving towards a careful selection of subgroups or subtypes of patients that have to be treated with each one of the available second-line targeted drugs. For this relevant unmet medical need, many laboratories and pharmaceutical companies have focused on developing new biomarkers and new drugs to fight anti-angiogenic resistance, but up to date, there is no proven established biomarker or method to predict which patient’s tumor is resistant to antiangiogenic therapies and which drug is capable of blocking this resistance to therapy. AngioResist PoC aims at solving the existing patient selection gap in the treatment of cancer that is therapeutically resistant to antiangiogenic drugs. Based on data generated from our ERC project and two filed European Patent applications, AngioResist PoC will transform the acquired basic knowledge into an Innovation project, to validate a novel biomarker of response/resistance to antiangiogenics together with a new inhibitor for the treatment of these selected patients. The project will coordinately perform the preclinical phases of development of the drug compound and the biomarker, with the final aim of licensing them both to a selected partner during the clinical phases. Together with our licensee, we aim at the final distribution of a therapeutic drug that will be delivered with a biomarker kit for the selection and treatment of cancer patients resistant to antiangiogenic drugs.

149 932 €

Start date: 2016-09-01, End date: 2018-02-28

In many European countries with ostensibly liberal abortion laws, women face legal restrictions to abortion beyond the first trimester of pregnancy, as well as other barriers to legal abortion, in particular shortages of providers willing and able to offer abortion due to poor training and to conscientious objection among physicians. The Council of Europe has recognized that conscientious objection can make access to safe abortion more difficult or impossible, particularly in rural areas and for low income women, who are forced to travel far to seek abortion care, including abroad. The WHO also highlights that delaying abortion care increases risks for women’s reproductive health. Despite the relevance of this topic from a public health and human rights perspective, the impact of procedural and social barriers to legal abortion on women in countries with ostensibly liberal abortion laws has not been studied by social scientists in Europe. This five-year research project is envisaged as a ground-breaking multi-disciplinary, mixed-methods investigation that will fill this gap, by capitalizing on previous, pioneer anthropological research of the PI on abortion and conscientious objection. It will contribute to the anthropology of reproduction in Europe, and particularly to the existing literature on abortion, conscientious objection and the medicalization of reproduction, and to the international debate on gender inequalities and citizenship, by exploring how barriers to legal abortion are constructed and how women embody and challenge them in different countries, by travelling or seeking illegal abortion, as well as their conceptualizations of abortion and their self perception as moral/political subjects. The project will be carried out in France, Italy and Spain, where the few existing studies show that women face several barriers to legal abortion as well as in the UK, the Netherlands and Spain, where Italian and French women travel to seek abortion care.

1 495 753 €

Start date: 2016-10-01, End date: 2021-09-30

The two fundamental challenges of this project are the integration of medieval Jewries and their histories within the framework of European history without undermining their distinct communal status and the creation of a history of everyday medieval Jewish life that includes those who were not part of the learned elite. The study will focus on the Jewish communities of northern Europe (roughly modern Germany, northern France and England) from 1100-1350. From the mid-thirteenth century these medieval Jewish communities were subject to growing persecution. The approaches proposed to access daily praxis seek to highlight tangible dimensions of religious life rather than the more common study of ideologies to date. This task is complex because the extant sources in Hebrew as well as those in Latin and vernacular were written by the learned elite and will require a broad survey of multiple textual and material sources. Four main strands will be examined and combined: 1. An outline of the strata of Jewish society, better defining the elites and other groups. 2. A study of select communal and familial spaces such as the house, the synagogue, the market place have yet to be examined as social spaces. 3. Ritual and urban rhythms especially the annual cycle, connecting between Jewish and Christian environments. 4. Material culture, as objects were used by Jews and Christians alike. Aspects of material culture, the physical environment and urban rhythms are often described as “neutral” yet will be mined to demonstrate how they exemplified difference while being simultaneously ubiquitous in local cultures. The deterioration of relations between Jews and Christians will provide a gauge for examining change during this period. The final stage of the project will include comparative case studies of other Jewish communities. I expect my findings will inform scholars of medieval culture at large and promote comparative methodologies for studying other minority ethnic groups

1 941 688 €

Start date: 2016-11-01, End date: 2021-10-31

The global marine ecosystem is being deeply altered by human activity. On the one hand, rising concentrations of atmospheric greenhouse gases are changing the physical and chemical state of the ocean, exerting pressure from the bottom up. Meanwhile, the global fishery has provided large economic benefits, but in so doing has restructured ecosystems by removing most of the large animal biomass, a major top-down change. Although there has been a tremendous amount of research into isolated aspects of these impacts, the development of a holistic understanding of the full interactions between physics, chemistry, ecology and economic activity might appear impossible, given the myriad complexities. This proposal lays out a strategy to assemble a team of trans-disciplinary expertise, that will develop a unified, data-constrained, grid-based modeling framework to represent the most important interactions of the global human-ocean system. Building this framework requires solving a series of fundamental problems that currently hinder the development of the full model. If these problems can be solved, the resulting model will reveal novel emergent properties and open the doors to a range of previously unexplored questions of high impact across a range of disciplines. Key questions include the ways in which animals interact with oxygen minimum zones with implications for fisheries, the impacts fish harvesting may have on nutrient recycling, spatio-temporal interactions between managed and unmanaged fisheries, and fundamental questions about the relationships between fish price, fishing cost, and multiple markets in a changing world. Just as the first coupled ocean-atmosphere models revealed a wealth of new behaviours, the coupled human-ocean model proposed here has the potential to launch multiple new fields of enquiry. It is hoped that the novel approach will contribute to a paradigm shift that treats human activity as one component within the framework of the Earth System.

1 600 000 €

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

In order to celebrate mathematics in the new millennium, the Clay Mathematics Institute established seven $1.000.000 Prize Problems. One of these is the conjecture of Birch and Swinnerton-Dyer (BSD), widely open since the 1960's. The main object of this proposal is developing innovative and unconventional strategies for proving groundbreaking results towards the resolution of this problem and their generalizations by Bloch and Kato (BK). Breakthroughs on BSD were achieved by Coates-Wiles, Gross, Zagier and Kolyvagin, and Kato. Since then, there have been nearly no new ideas on how to tackle BSD. Only very recently, three independent revolutionary approaches have seen the light: the works of (1) the Fields medalist Bhargava, (2) Skinner and Urban, and (3) myself and my collaborators. In spite of that, our knowledge of BSD is rather poor. In my proposal I suggest innovating strategies for approaching new horizons in BSD and BK that I aim to develop with the team of PhD and postdoctoral researchers that the CoG may allow me to consolidate. The results I plan to prove represent a departure from the achievements obtained with my coauthors during the past years: I. BSD over totally real number fields. I plan to prove new ground-breaking instances of BSD in rank 0 for elliptic curves over totally real number fields, generalizing the theorem of Kato (by providing a new proof) and covering many new scenarios that have never been considered before. II. BSD in rank r=2. Most of the literature on BSD applies when r=0 or 1. I expect to prove p-adic versions of the theorems of Gross-Zagier and Kolyvagin in rank 2. III. Darmon's 2000 conjecture on Stark-Heegner points. I plan to prove Darmon’s striking conjecture announced at the ICM2000 by recasting it in terms of special values of p-adic L-functions.

1 428 588 €

Start date: 2016-09-01, End date: 2021-08-31

Clinical experience with globally-acting cannabinoid-1 receptor (CB1R) antagonists revealed the benefits of blocking CB1Rs for the treatment of obesity and diabetes. However, their use is hampered by increased CNS-mediated side effects. Recently, I have demonstrated that peripherally-restricted CB1R antagonists have the potential to treat the metabolic syndrome without eliciting these adverse effects. While these results are promising and are currently being developed into the clinic, our ability to rationally design CB1R blockers that would target a diseased organ is limited. The current proposal aims to develop and test cell- and organelle-specific CB1R antagonists. To establish this paradigm, I will focus our interest on the kidney, since chronic kidney disease (CKD) is the leading cause of increased morbidity and mortality of patients with diabetes. Our first goal will be to characterize the obligatory role of the renal proximal tubular CB1R in the pathogenesis of diabetic renal complications. Next, we will attempt to link renal proximal CB1R with diabetic mitochondrial dysfunction. Finally, we will develop proximal tubular (cell-specific) and mitochondrial (organelle-specific) CB1R blockers and test their effectiveness in treating CKD. To that end, we will encapsulate CB1R blockers into biocompatible polymeric nanoparticles that will serve as targeted drug delivery systems, via their conjugation to targeting ligands. The implications of this work are far reaching as they will (i) point to renal proximal tubule CB1R as a novel target for CKD; (ii) identify mitochondrial CB1R as a new player in the regulation of proximal tubular cell function, and (iii) eventually become the drug-of-choice in treating diabetic CKD and its comorbidities. Moreover, this work will lead to the development of a novel organ-specific drug delivery system for CB1R blockers, which could be then exploited in other tissues affected by obesity, diabetes and the metabolic syndrome.

1 500 000 €

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

An innovative methodology has been developed in the field of copper-catalyzed cross coupling catalysis, with the goal of developing more efficient and sustainable synthetic protocols used by Chemical and Pharmaceutical Industries. Successful research developed within the ERC-2011-StG-277801 project has led to discover new methodologies for sustainable catalytic transformations using copper catalysts to form C-C or C-heteroatom bonds, finding out the feasibility of uncommon copper(III) species as key intermediates. This new methodology features three main advantages: a) Precise design of the auxiliary ligands used in these transformations is a pathway of a more sustainable reactivity; b) competitive alternative to the price and toxicity disadvantages of Pd-based catalysts; and c) it can impart distinct selectivity that will broaden the scope of synthetic tools. The goal of the present CatalApp project is to study the feasibility of bringing this technology into a pre-commercial stage, with the aim of accelerating the access to the market of this new methodology. The pre-commercial stage will be orientated into: 1) A technical perspective that will be achieved by scaling-up current gram-scale methodologies to kilogram scale procedures. 2) An Economic and legal perspective, which include an analysis of Intellectual Property (IP) protection needs, evaluation of patent filling procedures required to provide an adequate protection of the different developed methodologies, a market study to identify specific potential uses of these synthetic tools, and a review of potential commercialisation partners. The expected outcomes of the PoC project will be the commercial availability of a portfolio of synthetic methodologies based on Copper, designed for specific applications. The strive of the CatalApp PoC project is making available these new methodologies in response to the demand of the industry and investors in order to ensure its results will be exploited successfully.

147 500 €

Start date: 2016-08-01, End date: 2018-01-31

We propose to carry out a project which will produce a decisive step towards improving the accuracy of the Hubble constant as determined from the Cepheid-SN Ia method to 1%, by using 28 extremely rare eclipsing binary systems in the LMC which offer the potential to determine their distances to 1%. To achieve this accuracy we will reduce the main error in the binary method by interferometric angular diameter measurements of a sample of red clump stars which resemble the stars in our binary systems. We will check on our calibration with similar binary systems close enough to determine their orbits from interferometry. We already showed the feasibility of our method which yielded the best-ever distance determination to the LMC of 2.2% from 8 such binary systems. With 28 systems and the improved angular diameter calibration we will push the LMC distance uncertainty down to 1% which will allow to set the zero point of the Cepheid PL relation with the same accuracy using the large available LMC Cepheid sample. We will determine the metallicity effect on Cepheid luminosities by a) determining a 2% distance to the more metal-poor SMC with our binary method, and by b) measuring the distances to LMC and SMC with an improved Baade-Wesselink (BW) method. We will achieve this improvement by analyzing 9 unique Cepheids in eclipsing binaries in the LMC our group has discovered which allow factor- of-ten improvements in the determination of all basic physical parameters of Cepheids. These studies will also increase our confidence in the Cepheid-based H0 determination. Our project bears strong synergy to the Gaia mission by providing the best checks on possible systematic uncertainties on Gaia parallaxes with 200 binary systems whose distances we will measure to 1-2%. We will provide two unique tools for 1-3 % distance determinations to individual objects in a volume of 1 Mpc, being competitive to Gaia already at a distance of 1 kpc from the Sun.

2 360 500 €

Start date: 2016-11-01, End date: 2021-10-31

The ERC-funded project BIDECASEOX ERC-239910 has produced a series of chiral catalysts with broad applicability in various commercial fields associated with synthetic organic chemistry. These catalysts are based in earth abundant metals and activate hydrogen peroxide to perform asymmetric introduction of oxygen atoms into readily available and cheap non chiral organic molecules, producing highly valuable chiral products, leaving water as the only byproduct. By virtue of these reactions, valuable chiral products that nowadays are only accessible by expensive enzymatic methods, or in some cases by toxic, expensive and large waste-producing traditional stoichiometric oxidants, become available in a sustainable manner. Pharmaceutical and agricultural industry, polymer chemistry and fine chemistry are envisioned as potential targets for the interest of the catalysts. With the aim of accelerating their access to the market, the present Proof of Concept (PoC) project, named CHIROXCAT, will target to study the feasibility of bringing these catalysts into a pre-commercial stage. This will be achieved by scaling-up current mg-scale synthetic methods, in order to establish economically optimized multigram scale procedures, and by validating their use in the production of representative chiral molecules of potential interest to the fine chemical industry. This PoC activity will also include an analysis of intellectual property (IP) protection needs within the field of application, as well as setting up the basis for any patent filling procedure required to provide an adequate protection of the catalysts and their uses. Moreover, a market study will be conducted to identify specific potential uses of these compounds, and a review of potential commercialisation partners will be carried out. The expected outcomes of the PoC project will be the commercial availability of a portfolio of chiral catalysts based in earth abundant metals with application in chemical

149 750 €

Start date: 2016-05-01, End date: 2017-10-31