ERC FUNDED PROJECTS

NK cells that are well known by their ability to recognize and eliminate virus infected and tumor cells were also implicated in the defence against bacteria. However, the recognition of bacteria by NK cells is only poorly understood. we do not know how bacteria are recognized and the functional consequences of such recognition are also weakly understood. In the current proposal we aimed at determining the “NK cell receptor-bacterial interactome”. We will examine the hypothesis that NK inhibitory and activating receptors are directly involved in bacterial recognition. This ground breaking hypothesis is based on our preliminary results in which we show that several NK cell receptors directly recognize various bacterial strains as well as on a few other publications. We will generate various mice knockouts for NCR1 (a major NK killer receptor) and determine their microbiota to understand the physiological function of NCR1 and whether certain bacterial strains affects its activity. We will use different human and mouse NK killer and inhibitory receptors fused to IgG1 to pull-down bacteria from saliva and fecal samples and then use 16S rRNA analysis and next generation sequencing to determine the nature of the bacteria species isolated. We will identify the bacterial ligands that are recognized by the relevant NK cell receptors, using bacterial random transposon insertion mutagenesis approach. We will end this research with functional assays. In the wake of the emerging threat of bacterial drug resistance and the involvement of bacteria in the pathogenesis of many different chronic diseases and in shaping the immune response, the completion of this study will open a new field of research; the direct recognition of bacteria by NK cell receptors.

2 499 800 €

Start date: 2013-03-01, End date: 2018-02-28

Next generation sequencing (NGS) is revolutionizing all fields of biological research but it fails to extract the full range of information associated with genetic material and is lacking in its ability to resolve variations between genomes. The high degree of genome variation exhibited both on the population level as well as between genetically “identical” cells (even in the same organ) makes genetic and epigenetic analysis on the single cell and single genome level a necessity. Chromosomes may be conceptually represented as a linear one-dimensional barcode. However, in contrast to a traditional binary barcode approach that considers only two possible bits of information (1 & 0), I will use colour and molecular structure to expand the variety of information represented in the barcode. Like colourful beads threaded on a string, where each bead represents a distinct type of observable, I will label each type of genomic information with a different chemical moiety thus expanding the repertoire of information that can be simultaneously measured. A major effort in this proposal is invested in the development of unique chemistries to enable this labelling. I specifically address three types of genomic variation: Variations in genomic layout (including DNA repeats, structural and copy number variations), variations in the patterns of chemical DNA modifications (such as methylation of cytosine bases) and variations in the chromatin composition (including nucleosome and transcription factor distributions). I will use physical extension of long DNA molecules on surfaces and in nanofluidic channels to reveal this information visually in the form of a linear, fluorescent “barcode” that is read-out by advanced imaging techniques. Similarly, DNA molecules will be threaded through a nanopore where the sequential position of “bulky” molecular groups attached to the DNA may be inferred from temporal modulation of an ionic current measured across the pore.

1 627 600 €

Start date: 2013-10-01, End date: 2018-09-30

The two fundamental challenges of this project are the integration of medieval Jewries and their histories within the framework of European history without undermining their distinct communal status and the creation of a history of everyday medieval Jewish life that includes those who were not part of the learned elite. The study will focus on the Jewish communities of northern Europe (roughly modern Germany, northern France and England) from 1100-1350. From the mid-thirteenth century these medieval Jewish communities were subject to growing persecution. The approaches proposed to access daily praxis seek to highlight tangible dimensions of religious life rather than the more common study of ideologies to date. This task is complex because the extant sources in Hebrew as well as those in Latin and vernacular were written by the learned elite and will require a broad survey of multiple textual and material sources. Four main strands will be examined and combined: 1. An outline of the strata of Jewish society, better defining the elites and other groups. 2. A study of select communal and familial spaces such as the house, the synagogue, the market place have yet to be examined as social spaces. 3. Ritual and urban rhythms especially the annual cycle, connecting between Jewish and Christian environments. 4. Material culture, as objects were used by Jews and Christians alike. Aspects of material culture, the physical environment and urban rhythms are often described as “neutral” yet will be mined to demonstrate how they exemplified difference while being simultaneously ubiquitous in local cultures. The deterioration of relations between Jews and Christians will provide a gauge for examining change during this period. The final stage of the project will include comparative case studies of other Jewish communities. I expect my findings will inform scholars of medieval culture at large and promote comparative methodologies for studying other minority ethnic groups

1 941 688 €

Start date: 2016-11-01, End date: 2021-10-31

Can we exploit insights from the remarkably lubricated surfaces of articular cartilage, to create lubricants that may alleviate osteoarthritis (OA), the most widespread joint disease, affecting millions? These, succinctly, are the challenges of the present proposal. They are driven by our recent finding that lubrication of destabilised joints leads to changes in gene-regulation of the cartilage-embedded chondrocytes to protect against development of the disease. OA alleviation is known to arise through orthopedically suppressing shear-stresses on the cartilage, and a central premise of this project is that, by reducing friction at the articulating cartilage through suitable lubrication, we may achieve the same beneficial effect on the disease. The objectives of this project are to better understand the origins of cartilage boundary lubrication through examination of friction-reduction by its main molecular components, and exploit that understanding to create lubricants that, on intra-articular injection, will lubricate cartilage sufficiently well to achieve alleviation of OA via gene regulation. The project will examine, via both nanotribometric and macroscopic measurements, how the main molecular species implicated in cartilage lubrication, lipids, hyaluronan and lubricin, and their combinations, act together to form optimally lubricating boundary layers on model surfaces as well as on excised cartilage. Based on this, we shall develop suitable materials to lubricate cartilage in joints, using mouse models. Lubricants will further be optimized with respect to their retention in the joint and cartilage targeting, both in model studies and in vivo. The effect of the lubricants in regulating gene expression, in reducing pain and cartilage degradation, and in promoting stem-cell adhesion to the cartilage will be studied in a mouse model in which OA has been induced. Our results will have implications for treatment of a common, debilitating disease.

2 499 944 €

Start date: 2017-09-01, End date: 2022-08-31