ERC FUNDED PROJECTS

My project is to write a history of the formation of Islam using the vastly important but largely neglected papyri from Egypt. Until the introduction of paper in the 10th C., papyrus was the Mediterranean world’s primary writing material. Thousands of papyrus documents survive, preserving a minutely detailed transcription of daily life, as well as the only contemporary records of Islam’s rise and first wave of conquests. As an historian and papyrologist, my career has been dedicated to developing the potential of this extraordinary resource. The prevailing model of Islam’s formation is based on sources composed by a literary élite some 150 years after the events they describe. The distortions this entails are especially problematic since it was in these first two centuries that Islam’s institutional, social and religious framework developed and stabilised. To form a meaningful understanding of this development requires tackling the contemporary documentary record, as preserved in the papyri. Yet the technical difficulties presented by these mostly unpublished and uncatalogued documents have largely barred their use by historians. This project is a systematic attempt to address this critical problem. The project has three stages: 1) a stocktaking of unedited Arabic, Coptic and Greek papyri; 2) the editing of a corpus of the most significant papyri; 3) the presentation of a synthetic historical analysis through scholarly publications and a dedicated website. By examining the impact of Islam on the daily life of those living under its rule, the goal of this project is to understand the striking newness of Islamic society and its debt to the diverse cultures it superseded. Questions will be the extent, character and ambition of Muslim state competency at the time of the Islamic conquest; the steps – military, administrative and religious – by which it extended its reach and what this tells us about the origins and evolution of Muslim ideas of rulership, religion and pow

1 000 000 €

Start date: 2009-03-01, End date: 2015-02-28

Multiple Sclerosis (MS), an autoimmune demyelinating disease affecting the central nervous system (CNS), causes tremendous disability in young adults and inflicts huge economic burden on the society. The incidence of MS is steadily increasing in many countries arguing for environmental factors driven changes in disease induction. How and which environmental factors contribute to disease initiation and progression is unknown. Using a spontaneous mouse model of MS, we have shown that the gut microbiota is essential in triggering CNS autoimmunity. In contrast to the mice housed in conventional housing conditions, germ free (GF) mice, devoid of gut bacteria, were protected from spontaneous experimental autoimmune encephalomyelitis (sEAE). Re-colonization of GF mice with a complex regular gut flora derived from specific pathogen free (SPF) mice resulted in sEAE within 2-3 months. The re-colonization also triggered pro-inflammatory T and B cell responses. However, colonization of GF mice with a reduced gut flora failed to induce sEAE during our observation period suggesting a “specific” rather than a “broader” microbial trigger. In this proposal, I want to study the role of gut microbiota in CNS autoimmunity with the following aims: Aim 1: CNS autoimmunity triggering/protecting gut microbes and host immune responses I want to study how and which gut bacterial species are modulating CNS autoimmunity to better understand the origin of autoimmune responses and their relation to host immune responses. Aim 2: Molecular mechanisms of sensing of gut microbiota and microbial metabolites during CNS autoimmunity I want to identify the molecular pathways that are involved in sensing the gut microbiota and its metabolites which are relevant to CNS autoimmunity. Aim 3: Therapeutic application of gut microbiota for CNS autoimmunity I want to identify therapeutic strategies targeting gut microbiota to limit the development of inflammatory processes during CNS autoimmunity.

1 499 946 €

Start date: 2015-06-01, End date: 2020-05-31

In vertebrates, a receptor-based, innate sensing machinery is used to detect the presence of microbederived molecules or the perturbation microbial infection causes within the host. In the context of viral infection, non-self nucleic acids are sensed by a set of intracellular receptors that upon activation initiate broad antiviral effector responses to eliminate the imminent threat. Over the past years our understanding of these processes has considerably grown, mainly by employing murine knockout models. Recent advances in genome engineering now provide the opportunity to knockout genes or even to perform functional genetic screens in human cells, providing a powerful means to validate and generate hypotheses. We have developed a high-throughput genome targeting and validation platform that allows us to tackle large-scale loss-of-function studies both at a polyclonal as well as an arrayed format. In addition, we have invested considerable efforts to render this technology applicable to study innate immune sensing and signalling pathways in the human system. GENESIS will combine these efforts to tackle pertinent questions in this field that could not have been addressed before: We will systematically dissect known nucleic acid sensing pathways in the human system to explore their unique roles, cooperativity or redundancy in detecting non-self nucleic acids. We will perform polyclonal, genome-wide loss-of-function screens to elucidate signalling events downstream of intracellular DNA and RNA sensing pathways and their roles in orchestrating antiviral effector mechanisms. Moreover, in a large-scale perturbation study, we will specifically address the role of the kinome in antiviral innate immune signalling pathways, exploring the role of its individual members and their epistatic relationships in orchestrating gene expression. Altogether, these studies will allow us to obtain insight into innate immune signalling pathways at unprecedented precision, depth and breadth.

1 970 000 €

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

Glioma is the most common and aggressive tumour of the brain and its most malignant form, glioblastoma multiforme, is nowadays virtually not curable. Very little is known about glioma genesis and progression at the molecular level and not much progress has been achieved in the treatment of this disease during the last years. The understanding of the molecular mechanisms involved in the biology of glioma is essential for the development of successful and rational therapeutic strategies. Our project aims to: 1- Study the role of the TGF-beta, Shh, Notch, and Wnt signal transduction pathways in glioma. These pathways have been implicated in glioma but still not much is known about their specific mechanisms of action. 2- Study of a cell population within the tumour mass that has stem-cell-like characteristics, the glioma stem cells, and how the four mentioned pathways regulate their biology. 3- Study the role of a transcription factor, FoxG1, that has an important oncogenic role in some gliomas and that it is regulated by the four mentioned pathways interconnecting some of them. Our approach will be based on a tight collaboration with clinical researchers of our hospital and the study of patient-derived tumours. We will analyse human biopsies, generate primary cultures of human tumour cells, isolate the stem-cell-like population of patient-derived gliomas and generate mouse models for glioma based on the orthotopical inoculation of human glioma stem cells in the mouse brain to generate tumours with the same characteristics as the original human tumour. In addition, we will also study genetically modified mouse models and established cell lines. We expect that our results will help understand the biology of glioma and cancer, and we aspire to translate our discoveries to a more clinical ambit identifying molecular markers of diagnosis and prognosis, markers of response to therapies, and unveil new therapeutic targets against this deadly disease.

1 566 000 €

Start date: 2008-08-01, End date: 2014-07-31