ERC FUNDED PROJECTS

Recent advances have shown that therapeutic manipulations of key cell-cell interactions can have dramatic clinical outcomes. Most notable are several early successes in cancer immunotherapy that target the tumor-T cell interface. However, these successes were only partial. This is likely because the few known interactions are just a few pieces of a much larger puzzle, involving additional signaling molecules and cell types. Dendritic cells (DCs), play critical roles in the induction/suppression of T cells. At early cancer stages, DCs capture tumor antigens and present them to T cells. However, in advanced cancers, the tumor microenvironment (TME) disrupts the crosstalk between DCs and T cells. We will take a multi-step approach to explore how the TME imposes a suppressive effect on DCs and how to reverse this hazardous effect. First, we will use single cell RNA-seq to search for genes in aggressive human and mouse ovarian tumors that are highly expressed in advanced tumors compared to early tumors and that encode molecules that suppress DC activity. Second, we will design a set of CRISPR screens to find genes that are expressed in DCs and regulate the transfer of the suppressive signals. The screens will be performed in the presence of suppressive molecules to mimic the TME and are expected to uncover many key genes in DCs biology. We will develop a new strategy to find synergistic combinations of genes to target (named Perturb-comb), thereby reversing the effect of local tumor immunosuppressive signals. Lastly, we will examine the effect of modified DCs on T cell activation and proliferation in-vivo, and on tumor growth. We expect to find: (1) Signaling molecules in the TME that affect the immune system. (2) New cytokines and cell surface receptors that are expressed in DCs and signal to T cells. (3) New key regulators in DC biology and their mechanisms. (4) Combinations of genes to target in DCs that reverse the TME’s hazardous effects.

1 500 000 €

Start date: 2018-01-01, End date: 2022-12-31

Bacterial pathogens remain a significant threat to global health, necessitating a better understanding of host-pathogen biology. While various evidence point to early infection as a key event in the eventual progression to disease, our recent preliminary data show that during this stage, highly adaptable and dynamic host cells and bacteria engage in complex, diverse interactions that contribute to well-documented heterogeneous outcomes of infection. However, current methodologies rely on measurements of bulk populations, thereby overlooking this diversity that can trigger different outcomes. This application focuses on understanding heterogeneity during the first stages of infection in order to reduce the complexity of these interactions into informative readouts of population physiology and predictors of infection outcome. We will apply multiparametric single-cell analysis to obtain an accurate and complete description of infection with the enteric intracellular pathogen Salmonella of macrophages in vitro, and in early stages of mice colonization. We will characterize the molecular details that underlie distinct infection outcomes of individual encounters, to reconstruct the repertoire of host and pathogen strategies that prevail at critical stages of early infection. We propose the following three objectives: (1) Develop methodologies to simultaneously profile host and pathogen transcriptional changes on a single cell level; 2) Characterizing the molecular details that underlie the formation of subpopulations during macrophage infection; and (3) Determine how host and pathogen encounters in vivo result in emergence of specialized subpopulations, recruitment of immune cells and pathogen dissemination. We anticipate that this work will fundamentally shift our paradigms of infectious disease pathogenesis and lay the groundwork for the development of a new generation of therapeutic agents targeting the specific host-pathogen interactions ultimately driving disease.

1 499 999 €

Start date: 2017-10-01, End date: 2022-09-30

For decades the Holocene has been considered a flat and “boring” epoch from the standpoint of paleomagnetism, mainly due to insufficient resolution of the available paleomagnetic data. However, recent archaeomagnetic data have revealed that the Holocene geomagnetic field is anything but stable – presenting puzzling intervals of extreme decadal-scale fluctuations and unexpected departures from a simple dipolar field structure. This new information introduced an entirely new paradigm to the study of the geomagnetic field and to a wide range of research areas relying on paleomagnetic data, such as geochronology, climate research, and geodynamo exploration. This proposal aims at breaking the resolution limits in paleomagnetism, and providing a continuous time series of the geomagnetic field vector throughout the Holocene at decadal resolution and unprecedented accuracy. To this end I will use an innovative assemblage of data sources, jointly unique to the Levant, including rare archaeological finds, annual laminated stalagmites, varved sediments, and arid playa deposits. Together, these sources can provide unprecedented yearly resolution, whereby the “absolute” archaeomagnetic data can calibrate “relative” terrestrial data. The geomagnetic data will define an innovative absolute geomagnetic chronology that will be used to synchronize cosmogenic 10Be data and an extensive body of paleo-climatic indicators. With these in hand, I will address four ground-breaking problems: I) Chronology: Developing dating technique for resolving critical controversies in Levantine archaeology and Quaternary geology. II) Geophysics: Exploring fine-scale geodynamo features in Earth’s core from new generations of global geomagnetic models. III) Cosmogenics: Correlating fast geomagnetic variations with cosmogenic isotope production rate. IV) Climate: Testing one of the most challenging controversial questions in geomagnetism: “Does the Earth's magnetic field play a role in climate changes?”

1 786 381 €

Start date: 2018-11-01, End date: 2023-10-31

Contemporary scholarship has often envisioned modernity as a kind of immense cultural earthquake, originating somewhere in western or central Europe, and then gradually propagating throughout the continent. This massive upheaval is said to have shaken the very foundations of every culture it frequented, subsequently eliminating the world which once was, to make way for a new age. This project offers a new understanding of modernization, not as a radical break with tradition, but as the careful importation of new ideas by often timid, almost inadvertent innovators. The project focuses on the rich corpus of translations of non-Jewish texts into Jewish languages, which developed during the early modern period. Largely neglected by modern scholars, these translations played a pivotal role in fashioning Jewish culture from the sixteenth century into modern times. Jewish translators were never merely passive recipients of their non-Jewish sources; they mistranslated both deliberately and accidentally, added and omitted, and harnessed their sources to meet their own unique agendas. Throughout the process of translation then, a new corpus was created, one that was distinctly Jewish in character, but closely corresponded with the surrounding majority culture. JEWTACT offers the first comprehensive study of the entire gamut of these early modern Jewish translations, exposing a hitherto unexplored terrain of surprising intercultural encounters which took place upon the advent of modernity—between East and West, tradition and innovation, Christians and Jews. The project posits translation as the primary and most ubiquitous mechanism of Christian-Jewish cultural transfer in early modern Europe. In so doing, I wish to revolutionize our understanding of the so-called early modern “Jewish book,” revealing its intensely porous, collaborative and innovative nature, and to offer a new paradigm of Jewish modernization and cultural exchange.

1 496 900 €

Start date: 2019-02-01, End date: 2024-01-31