ERC FUNDED PROJECTS

Herpesviruses cause serious diseases in humans and animals. After initial lytic infection, herpesviruses establish a quiescent (latent) infection, which allows their persistence in the host for life. We and others recently identified a novel mechanism that allows maintenance of the genome of certain herpesviruses during latency, by integrating their complete genetic material into host telomeres. One of these viruses is human herpesvirus 6 (HHV-6) which is associated with seizures, encephalitis, and graft rejection in transplant patients. Sporadic reactivation of the integrated virus ensures continued evolution of the virus as it spreads to a new cadre of susceptible individuals. There are critical gaps in our knowledge regarding the fate of herpesvirus genomes during integration and reactivation as well as of viral and cellular factors involved in these processes. INTEGHER will make use of novel technologies to close these gaps and to devise new therapeutic approaches. Specifically, we will 1) determine the fate of the HHV-6 genome during latency by developing a novel reporter system that allows live-cell imaging of the virus genome in living cells and elucidate epigenetic changes of the HHV-6 genome during integration and reactivation; 2) identify viral and cellular factors that drive virus genome integration and reactivation, using recombinant viruses, drugs and CRISPR/Cas9 genome engineering 3) employ genome-editing tools to eliminate the virus genome integrated in host chromosomes in vitro and in an in vivo model. The proposal utilizes state-of-the-art technologies and pioneers new approaches, particularly with regard to visualization and excision of virus genomes in latently infected cells that are also present in (bone marrow) transplants. Altogether, these studies will define the mechanism of herpesvirus integration and reactivation and will provide new tools for therapeutic excision of virus genomes from living cells.

1 810 747 €

Start date: 2016-04-01, End date: 2022-03-31

Our current ability to map T-cell reactivity to certain molecular patterns poorly matches the huge diversity of T-cell recognition in humans. Our immune system holds approximately 107 different T-cell populations patrolling our body to fight intruding pathogens. Current state-of-the-art T-cell detection enables the detection of 45 different T-cell specificities in a given sample. Therefore comprehensive analysis of T-cell recognition against intruding pathogens, auto-immune attacked tissues or cancer is virtually impossible. To gain insight into immune recognition and allow careful target selection for disease intervention, also on a personalized basis, we need technologies that allow detection of vast numbers of different T-cell specificities with high sensitivity in small biological samples. I propose here a new technology based on multimerised peptide-major histocompatibility complex I (MHC I) reagents that allow detection of >1000 different T-cell specificities with high sensitivity in small biological samples. I will use this new technology to gain insight into the T-cell recognition of cancer cells and specifically assess the impact of mutation-derived neo-epitopes on T cell-mediated cancer cell recognition. A major advantage of this new technology relates to the ability of coupling the antigen specificity to the T-cell receptor sequence. This will enable us to retrieve information about T-cell receptor sequences coupled with their molecular recognition pattern, and develop a predictor of binding between T-cell receptors and specific epitopes. It will ultimately enable us to predict immune recognition based on T-cell receptor sequences, and has the potential to truly transform our understanding of T cell immunology. Advances in our understanding of T cell immunology are leading to massive advances in the treatment of cancer. The technologies I propose to develop and validate will greatly aid this process and have application for all immune related diseases.

1 499 070 €

Start date: 2016-06-01, End date: 2021-05-31

Metabolic syndrome and osteoporosis are the two metabolic diseases with the highest and most rapidly growing prevalence, transforming them into a major global health and socioeconomic concern. Metabolic syndrome can be diagnosed with established biomarkers, but the selection of optimal prevention strategies for each individual patient is still problematic. Osteoporosis can be treated, but its current early diagnosis remains insufficient. The two diseases have been linked through the role of fat. Fat is central to their incidence and progression, and the probing of fat cellular properties can provide groundbreaking solutions for overcoming the existing challenges in the diseases early diagnosis and prevention. In metabolic syndrome, there is evidence supporting a role of brown fat in preventing the disease. Brown fat has different microstructure than white fat. However, there is no established non-invasive biomarker to measure brown fat. In osteoporosis, there is evidence supporting a role of marrow fat, in combination with bone mineral density, for monitoring fracture risk. However, there is no non-invasive biomarker to measure marrow fat cellular changes in osteoporosis. Magnetic resonance imaging (MRI) is the ideal modality for non-invasively measuring fat throughout the body. In order to differentiate brown from white fat and characterize the relationship between bone mineral and marrow fat cells, the employed MR methodology needs a technical breakthrough, shifting from the state-of-the-art water-centered paradigm to a fat-centered microstructural MRI paradigm. ProFatMRI describes an innovative research program that aims to develop and ex vivo validate diffusion and susceptibility MRI biomarkers of fat microstructure, and in vivo apply them at clinical MRI systems. The resulting technologies will provide novel ways for selecting optimal individualized prevention strategies in metabolic syndrome and for achieving reliable risk fracture prediction in osteoporosis.

1 499 566 €

Start date: 2016-04-01, End date: 2021-07-31

The Internet has revolutionalized the way people and corporations communicate, publish, access, and search for information. As our globally-connected digital civilization increasingly relies on its smooth operation any disruption has a direct negative impact on both the economy and society. However, the Internet was not designed to serve its current role nor was foreseen to be a public good. On the contrary, it was designed to be fully decentralized and thus administrated by the owners of independent networks. Today, the various Internet players have diverse and often conflicting objectives. Indeed, the tussle between Internet players or between them and governments hit the news and the negative externalities affect the life of potentially billions of Internet users worldwide and harm innovation in the Internet. We propose a research agenda to resolve the tussle in the Internet. First, we propose the use of sophisticated techniques to collect and analyze massive network data to unveil the complex interactions among the various Internet players that lead to disputes and to identify the conditions under which conditions a resolution is possible. Second, we utilize additional degrees of freedom to resolve the tussle in the Internet by enabling coordination of the various Internet players. To this end, we introduce expressiveness of all the involved parties in existing and emerging protocols and enable agile deployment of third-party services and applications inside operational networks. Third, we contribute to the Internet policy making debate by providing an unbiased view of the state and health of the Internet as well as providing recommendations on how to resolve the Internet tussle. This is an interdisciplinary effort to foster a dialogue for Internet's future and sustainability in light of its ever-increasing growth and competitiveness.

1 499 875 €

Start date: 2017-02-01, End date: 2022-01-31