ERC FUNDED PROJECTS

Heart failure (HF) is the ultimate outcome of many cardiovascular diseases. Re-expression of fetal genes in the adult heart contributes to development of HF. Two mechanisms involved in the control of gene expression are epigenetics and microRNAs (miRs). We propose a project on epigenetic and miR-mediated mechanisms leading to HF. Epigenetics refers to heritable modification of DNA and histones that does not modify the genetic code. Depending on the type of modification and on the site affected, these chemical changes up- or down-regulate transcription of specific genes. Despite it being a major player in gene regulation, epigenetics has been only partly investigated in HF. miRs are regulatory RNAs that target mRNAs for inhibition. Dysregulation of the cardiac miR signature occurs in HF. miR expression may itself be under epigenetic control, constituting a miR-epigenetic regulatory network. To our knowledge, this possibility has not been studied yet. Our specific hypothesis is that the profile of DNA/histone methylation and the cross-talk between epigenetic enzymes and miRs have fundamental roles in defining the characteristics of cells during cardiac development and that the dysregulation of these processes determines the deleterious nature of the stressed heart’s gene programme. We will test this first through a genome-wide study of DNA/histone methylation to generate maps of the main methylation modifications occurring in the genome of cardiac cells treated with a pro-hypertrophy regulator and of a HF model. We will then investigate the role of epigenetic enzymes deemed important in HF, through the generation and study of knockout mice models. Finally, we will test the possible therapeutic potential of modulating epigenetic genes. We hope to further understand the pathological mechanisms leading to HF and to generate data instrumental to the development of diagnostic and therapeutic strategies for this disease.

2 500 000 €

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

The possibility to artificially induce and expand in vitro tissue-specific stem cells (SCs) is an important goal for regenerative medicine, to understand organ physiology, for in vitro modeling of human diseases and many other applications. Here we found that this goal can be achieved in the culture dish by transiently inducing expression of YAP or TAZ - nuclear effectors of the Hippo and biomechanical pathways - into primary/terminally differentiated cells of distinct tissue origins. Moreover, YAP/TAZ are essential endogenous factors that preserve ex-vivo naturally arising SCs of distinct tissues. In this grant, we aim to gain insights into YAP/TAZ molecular networks (upstream regulators and downstream targets) involved in somatic SC reprogramming and SC identity. Our studies will entail the identification of the genetic networks and epigenetic changes controlled by YAP/TAZ during cell de-differentiation and the re-acquisition of SC-traits in distinct cell types. We will also investigate upstream inputs establishing YAP/TAZ activity, with particular emphasis on biomechanical and cytoskeletal cues that represent overarching regulators of YAP/TAZ in tissues. For many tumors, it appears that acquisition of an immature, stem-like state is a prerequisite for tumor progression and an early step in oncogene-mediated transformation. YAP/TAZ activation is widespread in human tumors. However, a connection between YAP/TAZ and oncogene-induced cell plasticity has never been investigated. We will also pursue some intriguing preliminary results and investigate how oncogenes and chromatin remodelers may link to cell mechanics, and the plasticity of the differentiated and SC states by controlling YAP/TAZ. In sum, this research should advance our understanding of the cellular and molecular basis underpinning organ growth, tissue regeneration and tumor initiation.

2 498 934 €

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

A growing number of scholars are studying the interactions between cultural values, social and religious norms, institutions, and economic outcomes. The rise of markets, as well as the development of contracts that enable mutually beneficial transactions among agents, are one of the central themes in the literature on long-term economic growth. This project contributes to both strands of literature by studying the invention and development of marine insurance contracts in medieval Italy and their subsequent spread all over Europe. It brings the economic approach to previously unexplored historical data housed in archives in Florence, Genoa, Pisa, Palermo, Prato, and Venice. The interest in the historical origin and development of marine insurance contracts is twofold. First, marine contracts are the “parents” of all the other insurance contracts (e.g., fire, life, health, etc) that were developed in subsequent centuries to cope with risk. Second, their invention, as well as other innovations in business practices in the Middle Ages, contributed to the growth of international trade in subsequent centuries. The key novelty of the project stems from combining contract theory with information from thousands of insurance contracts between 1300 and 1550 to explain why marine insurance developed in medieval Italy and then Europe, to study the empirical determinants of insurance contracts in medieval Italy, and to analyze how medieval merchants coped with adverse selection and moral hazard problems. Most scholars agree that marine insurance was unknown to the ancient world. Italian merchants developed the first insurance contracts and other innovations in business practices during and in the aftermath of the Commercial Revolution that swept Europe from roughly 1275 to about 1325. Marine insurance contracts may have developed as a spin-off of earlier contracts which shifted the risk from one party to another (e.g., sea loan, insurance loan). Alternatively, in the early or mid-fourteenth century, sedentary merchants that provided the capital to travelling merchants invented a new type of contract, when they discovered that the existing contract forms had shortcomings in transferring and dividing sea risk. A sample of the questions that this project will address includes: - Why did insurance contracts and a marine insurance market first develop in medieval times and not earlier despite merchants had to deal with the risks associated with maritime trade since antiquity? - What were the empirical determinants of contract form (e.g., insurance premium) in the medieval insurance market? - How did medieval merchants compute insurance premia without having the formal notion of probability that was developed only in the mid-seventeenth century? - How did medieval merchants cope with the typical problems that plague insurance markets, i.e., adverse selection and moral hazard?

1 113 900 €

Start date: 2012-07-01, End date: 2018-06-30

With the ENSURE project I aim at attaining ground-breaking results in the field of superintense laser-driven ion acceleration, proposing a multidisciplinary research program in which theoretical, numerical and experimental research will be coherently developed in a team integrating in an unprecedented way advanced expertise from materials engineering and nanotechnology, laser-plasma physics, computational science. The aim will be to bring this topic from the realm of fundamental basic science into a subject having realistic engineering applications. The discovery in 2000 of brilliant, multi-MeV, collimated ion sources from targets irradiated by intense laser pulses stimulated great interest worldwide, due to the ultra-compact spatial scale of the accelerator and ion beam properties. The laser-target system provides unique appealing features to fundamental physics which can be studied in a small lab. At the same time, laser-ion beams could have future potential in many technological areas. This is boosting the development of new labs and facilities all over Europe, but to support these efforts, crucial challenges need to be faced to make these applications a reality. The goals of ENSURE are: i) design and production of nanoengineered targets, with properties tailored to achieve optimized ion acceleration regimes. This will be pursued exploiting advanced techniques of material science & nanotechnology ii) design of laser-ion beams for novel, key applications in nuclear and materials engineering iii) realization of engineering-oriented ion acceleration experiments, in advanced facilities iv) synergic development of all the required theoretical support for i,ii,iii). The results of the project can determine a unique impact in the research on laser-driven ion acceleration in Europe, providing new directions to support the attainment, in the next future, of concrete applications of great societal relevance, in medical, energy and materials areas.

1 887 500 €

Start date: 2015-09-01, End date: 2020-08-31