ERC FUNDED PROJECTS

Diabetes has become one of the most widespread metabolic disorders with epidemic dimensions affecting almost 6% of the world’s population. Despite modern treatments, the life expectancy of patients with Type 1 diabetes remains reduced as compared to healthy subjects. There is therefore a need for alternative therapies. Towards this aim, using the mouse, we recently demonstrated that the in vivo forced expression of a single factor in pancreatic alpha-cells is sufficient to induce a continuous regeneration of alpha-cells and their subsequent conversion into beta-like cells, such converted cells being capable of reversing the consequences of chemically-induced diabetes in vivo (Collombat et al. Cell, 2009). The PI and his team therefore propose to further decipher the mechanisms involved in this alpha-cell-mediated beta-cell regeneration process and determine whether this approach may be applied to adult animals and whether it would efficiently reverse Type 1 diabetes. Furthermore, a major effort will be made to verify whether our findings could be translated to human. Specifically, we will use a tri-partite approach to address the following issues: (1) Can the in vivo alpha-cell-mediated beta-cell regeneration be induced in adults mice? What would be the genetic determinants involved? (2) Can alpha-cell-mediated beta-cell regeneration reverse diabetes in the NOD Type 1 diabetes mouse model? (3) Can adult human alpha-cells be converted into beta-like cells? Together, these ambitious objectives will most certainly allow us to gain new insight into the mechanisms defining the identity and the reprogramming capabilities of mouse and human endocrine cells and may thereby open new avenues for the treatment of diabetes. Similarly, the determination of the molecular triggers implicated in the beta-cell regeneration observed in our diabetic mice may lead to exciting new findings, including the identification of “drugable” targets of importance for human diabetic patients.

1 500 000 €

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

Imaging is one of the most powerful technique to visualize molecules, tissues, to understand and follow processes and it is the most used diagnostic tool in vitro and in vivo, Current biomedical imaging techniques can have high sensitivity, good spatial/temporal resolution and, in some cases, high tissue penetration but cannot combine all of these desired properties without using harmful radiations (or toxic labels) or very expensive equipment. Optical imaging techniques represent the best compromise among them; however, their ability to scale to human body is precluded. The main restriction of fluorescence imaging is that it requires light excitation which is limited by tissue absorption and scattering. Such limitations are not present in chemiluminescence imaging since light production occurs through a chemical reaction, resulting in higher penetration depth and best sensitivity. However both natural and artificial chemiluminescent systems require a continuous flow of exogenous reactants since all substrates are irreversibly consumed. BioPoweredCL aims to develop an unprecedented strategy to enable molecular imaging by realizing near infrared luminophores that harvest energy from the cellular respiration chain, in order to emit light without being consumed themselves. BioPoweredCL takes advantage of the most recent progress in artificial light production to develop a novel imaging technique where the absence of an excitation source overcomes the current limitations of fluorescence imaging while the regeneration of the luminophore overcomes the limitations of bioluminescence imaging. If successful it could replace current techniques based on harmful ionizing radiations such as X-rays or γ-rays. To reach such a grand-challenge the work plan is articulated into three different phases: 1) synthesis of new luminophores; 2) electrochemical characterization and energy cell harvesting; 3) in vitro experiments where the full potential of the approach will be validated.

1 449 750 €

Start date: 2021-10-01, End date: 2026-09-30

For over half a millennium, the great medieval capital of Angkor lay at the heart of a vast empire stretching across much of mainland SE Asia. Recent research has revealed that the famous monuments of Angkor were merely the epicentre of an immense settlement complex, with highly elaborate engineering works designed to manage water and mitigate the uncertainty of monsoon rains. Compelling evidence is now emerging that other temple complexes of the medieval Khmer Empire may also have formed the urban cores of dispersed, low-density settlements with similar systems of hydraulic engineering. Using innovative airborne laser scanning (‘lidar’) technology, CALI will uncover, map and compare archaeological landscapes around all the major temple complexes of Cambodia, with a view to understanding what role these complex and vulnerable water management schemes played in the growth and decline of early civilisations in SE Asia. CALI will evaluate the hypothesis that the Khmer civilisation, in a bid to overcome the inherent constraints of a monsoon environment, became locked into rigid and inflexible traditions of urban development and large-scale hydraulic engineering that constrained their ability to adapt to rapidly-changing social, political and environmental circumstances. By integrating data and techniques from fast-developing archaeological sciences like remote sensing, palaeoclimatology and geoinformatics, this work will provide important insights into the reasons for the collapse of inland agrarian empires in the middle of the second millennium AD, a transition that marks the emergence of modern mainland SE Asia. The lidar data will provide a comprehensive and internally-consistent archive of urban form at a regional scale, and offer a unique experimental space for evaluating socio-ecological resilience, persistence and transformation over two thousand years of human history, with clear implications for our understanding of contemporary urbanism and of urban futures.

1 482 844 €

Start date: 2015-03-01, End date: 2020-02-29

The emergence of resistance to chemotherapy and targeted therapies is a major challenge for the treatment of cancer. While several genetic mechanisms driving resistance processes have been discovered, non-genetic mechanisms have also been shown to contribute to drug resistance. Yet, our restricted understanding of epigenetic evolution has so far limited our ability to modulate resistance using epigenetic modifiers. With ChromTrace, our goal is to reconstruct and define the contribution of epigenetic evolution to chemo-resistance in triple-negative breast tumors. In this aggressive sub-type of breast cancer, chemotherapy is the standard of care, but chemo-resistance remains the major unmet clinical need. We will explore the heterogeneity of H3K27me3chromatin states - key determinant of cell identity - in tumor cells, study how they are transmitted and determine whether they are associated to the resistance phenotype. Combining lineage tracing and targeted sequencing to our original single-cell chromatin profiling approach, we will reconstruct the dynamics of chromatin features over time in the context of genetic evolution. In parallel, using a live-cell microscopy reporter system, we will evaluate the association of recurrent chromatin features with the resistance phenotype and elucidate mechanisms of epigenetic tumor evolution. Our results on the heritability and plasticity of chromatin landscapes will have strong impact on our understanding of epigenetic evolution in cancer. Our long-term goal is to build on this integrated appreciation of molecular tumor evolution processes to propose novel therapeutic strategies to control resistance to chemotherapy. Finally, our approaches being applicable to any dynamic biological system, ChromTrace opens the perspective to study evolution of chromatin landscapes not only in other types of cancer and disease, but also during normal development.

1 500 000 €

Start date: 2021-01-01, End date: 2025-12-31