ERC FUNDED PROJECTS

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

Interferometers are fundamental tools for the study of nature laws and for the precise measurement and control of the physical world. In the last century, the scientific and technological progress has proceeded in parallel with a constant improvement of interferometric performances. For this reason, the challenge of conceiving and realizing new generations of interferometers with broader ranges of operation and with higher sensitivities is always open and actual. Despite the introduction of laser devices has deeply improved the way of developing and performing interferometric measurements with light, the atomic matter wave analogous, i.e. the Bose-Einstein condensate (BEC), has not yet triggered any revolution in precision interferometry. However, thanks to recent improvements on the control of the quantum properties of ultra-cold atomic gases, and new original ideas on the creation and manipulation of quantum entangled particles, the field of atom interferometry is now mature to experience a big step forward. The system I want to realize is a Mach-Zehnder spatial interferometer operating with trapped BECs. Undesired decoherence sources will be suppressed by implementing BECs with tunable interactions in ultra-stable optical potentials. Entangled states will be used to improve the sensitivity of the sensor beyond the standard quantum limit to ideally reach the ultimate, Heisenberg, limit set by quantum mechanics. The resulting apparatus will show unprecedented spatial resolution and will overcome state-of-the-art interferometers with cold (non condensed) atomic gases. A successful completion of this project will lead to a new generation of interferometers for the immediate application to local inertial measurements with unprecedented resolution. In addition, we expect to develop experimental capabilities which might find application well beyond quantum interferometry and crucially contribute to the broader emerging field of quantum-enhanced technologies.

1 068 000 €

Start date: 2011-01-01, End date: 2015-12-31

This project will undertake the first systematic investigation of the various literary documents that circulated simultaneously in more than one language in Tuscany, and especially Florence, between the mid-13th Century and the beginning of 15th Century. During that period, Florence was both a prominent literary centre in the vernacular, and home to a renewal of classical Latin eloquence. While both fields are well studied, their interaction remains largely unexplored. This research, at the convergence of several disciplines (literature, philology, linguistics and medieval history), has a strong pioneering character. It aims at changing the perception of medieval Italian culture and interpretation of the break between medieval Culture and Humanism. For this reason, the project will develop research in varying degrees of depth. First, it will provide the first catalogue of bilingual texts and manuscripts of medieval Tuscany. Organized as a database, this tool of analysis will stir innovative research in this field, some of which will be immediately promoted during the project. Secondly, two case studies, considered as important and methodologically exemplary, will be researched in detail, through the publication of two important set of texts, of secular and religious nature : 1. The vernacular translation of the Latin Epistles of Dante Alighieri; 2. A collection of polemical, historiographical, devotional and prophetical documents produced by the Tuscan dissident Franciscans in last decades of the 14th Century. Finally, the entire team, led by the PI, will be involved in the preparation of a synthesis volume on Tuscan culture in the fourteenth century viewed through bilingualism, entitled Cartography of bilingual culture in Fourteenth-Century Tuscany. From this general map of the Italian culture of the time, no literary genre nor field (be it religious or lay) shall be excluded.

1 480 625 €

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

Challenging the notion of Fortress Europe , the research investigates relations between the European Union and its southern periphery through the concept of borderlands . The concept emphasises the disaggregation of the triple function of borders demarcating state territory, authority, and national identity inherent in the Westphalian model of statehood. This process is most visible in (although not limited to) Europe, where integration has led to supranational areas of sovereignty, an internal market, a common currency, and a zone of free movement of people, each with a different territorial span. The project explores the complex and differentiated process by which the EU extends its unbundled functional and legal borders to the so-called southern Mediterranean (North Africa and parts of the Middle East), thereby transforming it into borderlands . They connect the European core with the periphery through various legal and functional border regimes, governance patterns, and the selective outsourcing of some EU border control duties. The overarching questions informing this research is whether, first, the borderland policies of the EU, described by some as a neo-medieval empire, is a functional consequence of the specific integration model pursued inside the EU, a matter of foreign policy choice or a local manifestation of a broader global phenomenon. Second, the project addresses the question of power dynamics that underwrite borderland governance, presuming a growing leverage of third country governments resulting from their co-optation as gatekeepers. Thus, while adopting an innovative approach, the project will enhance our understanding of EU-Mediterranean relations while also addressing crucial theoretical questions in international relations.

1 353 920 €

Start date: 2011-10-01, End date: 2017-03-31