Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Lymph node homing of immune cells via afferent lymphatics – mechanisms and immune response (LYMPHATICS-HOMING)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Immunity and infection
Countries involved: Germany
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-04-01
End date: 2019-03-31
Duration (months): 72.0
Total project cost (EUR): 2491200.0
EU funding (EUR): 2491200.0
Participants: 1
Project status: CLOSED

The continuous migration of immune cells to lymph nodes (LN) is of utmost importance for the induction of both protective immunity as well as immunological tolerance. Despite this pivotal role, little is known regarding migration paths and the molecular cues regulating homing of immune cells that arrive via afferent lymphatic vessels to LN. This conspicuous lack of knowledge is primarily due to profound technical limitations. My team and I have recently developed a highly innovative technique of micromanipulator-guided injections into afferent lymph vessels that drain into the popliteal LN of living mice allowing precise delivery of very low numbers of cells into a LN. This approach, in combination with multicolor 2-photon in vivo microscopy, will now allow new and ground-breaking insights in routes, cellular and molecular mechanisms that regulate entry of cells reaching LNs via afferent lymphatics. Specifically, we aim to 1) characterize the homing potential of lymph-derived naïve B cells, naïve CD8 T cells, and regulatory T cells and study their contribution to LN homeostasis; 2) initiate and quantify primary immune responses to model antigens as well as pathogens mediated by naïve T cells that homed to LN via afferent lymphatics; 3) characterize memory immune responses mediated by different subpopulations of effector/memory cells that homed to LN via afferent lymphatics; 4) study the role of neutrophilic and eosinophilic granulocytes in adaptive immune responses; 5) identify homing molecules and mechanisms that allow DCs and metastasizing tumor cells to penetrate the floor of the LN subcapsular sinus. Results obtained from these studies will provide fundamentally new insights in processes that regulate immune cell homing to LN and the induction of primary and recall memory immune responses. Furthermore, this information will build a broad basis for the development of novel vaccination strategies and to understand how to interfere with tumor spread to LNs.

Keywords: lymphocyte homing,lymph node,chemokines
Identifying genes and pathways that drive molecular switches and back-up mechanisms between apoptosis and autophagy (DEATHSWITCHING)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Cellular and Developmental Biology
Countries involved: Israel
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-03-01
End date: 2018-02-28
Duration (months): 60.0
Total project cost (EUR): 2500000.0
EU funding (EUR): 2500000.0
Participants: 1
Project status: CLOSED

A cell’s decision to die is governed by multiple input signals received from a complex network of programmed cell death (PCD) pathways, including apoptosis and programmed necrosis. Additionally, under some conditions, autophagy, whose function is mainly pro-survival, may act as a back-up death pathway. We propose to apply new approaches to study the molecular basis of two important questions that await resolution in the field: a) how the cell switches from a pro-survival autophagic response to an apoptotic response and b) whether and how pro-survival autophagy is converted to a death mechanism when apoptosis is blocked. To address the first issue, we will screen for direct physical interactions between autophagic and apoptotic proteins, using the protein fragment complementation assay. Validated pairs will be studied in depth to identify built-in molecular switches that activate apoptosis when autophagy fails to restore homeostasis. As a pilot case to address the concept of molecular ‘sensors’ and ‘switches’, we will focus on the previously identified Atg12/Bcl-2 interaction. In the second line of research we will categorize autophagy-dependent cell death triggers into those that directly result from autophagy-dependent degradation, either by excessive self-digestion or by selective protein degradation, and those that utilize the autophagy machinery to activate programmed necrosis. We will identify the genes regulating these scenarios by whole genome RNAi screens for increased cell survival. In parallel, we will use a cell library of annotated fluorescent-tagged proteins for measuring selective protein degradation. These will be the starting point for identification of the molecular pathways that convert survival autophagy to a death program. Finally, we will explore the physiological relevance of back-up death mechanisms and the newly identified molecular mechanisms to developmental PCD during the cavitation process in early stages of embryogenesis.

Keywords: programmed cell death,autophagy,necrosis,protein-protein interactions,rnai screens,molecular switches,back-up mechanisms to cell death.
Identification and functional validation of drugable targets/pathways for triple negative breast cancer (TRIPLE-BC)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Diagnostic tools, therapies and public health
Countries involved: Netherlands,Netherlands
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-04-01
End date: 2018-03-31
Duration (months): 60.0
Total project cost (EUR): 2495101.56
EU funding (EUR): 2495101.56
Participants: 3
Project status: CLOSED

Patients suffering from triple-negative breast cancer (TNBC) have a poor prognosis as these tumors frequently confer resistance against chemotherapeutic agents and lack drug targets such as estrogen receptor, progesterone receptor, and epidermal growth factor receptor 2. Insufficient knowledge on the biology of this specific breast tumor type and its heterogeneity hinder the identification of potential novel drug targets. Lethality enhancer screening is an ideal approach to identify new drug targets in tumors with specific genetic aberrations. We plan to adapt this concept of synthetic lethality by anticipating that while TNBC cells confer resistance to available anticancer drugs, specific knock down of particular genes by RNA-interference (RNAi) may result in a synergistic cell killing. Another important aspect of our approach is that we will concentrate in our screens on the top 500 candidate genes shown to be crucial in TNBC for cellular processes. The genes will be prioritized by Bayesian network analysis on prior knowledge on clinical TNBC from our own extensive genomics and proteomics studies, the literature, next generation sequencing efforts, and databases listing drugability of targets. We will employ RNAi-based knock down of drugable targets in 22 cell lines to reveal genes essential for drug resistance in TNBC. In addition to 2D cultures, screens will also be applied to 3D cultures, which are thought to better reflect the in vivo situation. The most effective combinations for each TNBC subtype will further be functionally investigated in vitro and in vivo to unravel the molecular nature of the synthetic lethality. Finally, translational studies will be performed to establish the potential clinical relevance of the identified targets/pathways in large numbers of human TNBC and non-TNBC tumors on tissue microarrays. It is expected that the newly designed (combination) therapies result in a decline in TNBC mortality and reduction of healthcare costs.

Keywords: triple-negative breast cancer,drug targets,synthetic lethality screen,personalized medicine,systems biology,functional validation
The ecology of metabolic phenotypes: from cells to populations (METAPHEN)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Evolutionary, population and environmental biology
Countries involved: United Kingdom
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-05-01
End date: 2018-10-31
Duration (months): 66.0
Total project cost (EUR): 2253716.0
EU funding (EUR): 2253716.0
Participants: 1
Project status: CLOSED

Metabolic rate is a fundamental life history trait. Yet it also shows remarkable intra-specific variation: some individuals consistently have 2-3 times the maintenance costs of conspecifics the same size, age and sex. The predicted consequences of this variation are central to our understanding of optimal life history strategies and resource allocation trade-offs. But how is this intra-specific variation maintained? And why have attempts to link variation in metabolic rate to fitness yielded very inconsistent results? I propose that this is due to the focus having been on resting metabolism, with other aspects – most notably maximal metabolic rate and aerobic scope - being overlooked. There is pronounced variation in these two neglected components of metabolic profile, uncorrelated with that in resting metabolism, and increasing evidence that they may influence species distributions. I point out that these different components of metabolic rate are inextricably linked to levels of mitochondrial uncoupling, and hence to energy efficiency, potential oxidative stress and senescence. I predict that different microhabitats will favour specific combinations of metabolic traits, leading to spatial and temporal structuring of metabolic phenotypes within and across populations. This project aims to test this new framework in a multidisciplinary project that uses experimental manipulations at levels ranging from the cellular to the population. The project combines cellular analyses and cutting edge technology with carefully designed experiments in an ecological setting. I will test whether variability in metabolic traits is maintained through context-dependent fitness. If successful, the work will reveal how metabolic physiology is a key determinant of the ability of organisms to cope with variable environments, so explaining the persistence of variation in physiological traits and increasing our understanding of the likely consequences for organisms of environmental change.

Keywords: physiological ecology
Engineering an artificial immune system with functional components assembled from prokaryotic parts and modules (ARISYS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Applied life sciences and biotechnology
Countries involved: Spain
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-05-01
End date: 2019-04-30
Duration (months): 72.0
Total project cost (EUR): 2422271.0
EU funding (EUR): 2422271.0
Participants: 1
Project status: CLOSED

The objective of this project is to overcome current limitations for antibody production that are inherent to the extant immune system of vertebrates. This will be done by creating an all-in-one artificial/synthetic counterpart based exclusively on prokaryotic parts, devices and modules. To this end, ARISYS will exploit design concepts, construction hierarchies and standardization notions that stem from contemporary Synthetic Biology for the assembly and validation of (what we believe is) the most complex artificial biological system ventured thus far. This all-bacterial immune-like system will not only simplify and make affordable the manipulations necessary for antibody generation, but will also permit the application of such binders by themselves or displayed on bacterial cells to biotechnological challenges well beyond therapeutic and health-related uses. The work plan involves the assembly and validation of autonomous functional modules for [i] displaying antibody/affibody (AB) scaffolds attached to the surface of bacterial cells, [ii] conditional diversification of target-binding sequences of the ABs, [iii] contact-dependent activation of gene expression, [iv] reversible bi-stable switches, and [v] clonal selection and amplification of improved binders. These modules composed of stand-alone parts and bearing well defined input/output functions, will be assembled in the genomic chassis of streamlined Escherichia coli and Pseudomonas putida strains. The resulting molecular network will make the ABs expressed and displayed on the cell surface to proceed spontaneously (or at the user's decision) through subsequent cycles of affinity and specificity maturation towards antigens or other targets presented to the bacterial population. In this way, a single, easy-to-handle (albeit heavily engineered) strain will govern all operations that are typically scattered in a multitude of separate methods and apparatuses for AB production.

Keywords: affibodies,protein display,targeted mutagenesis,confinement sensing,light-triggered switches,bistability,pseudomonas,adhesion,vectors,standardization,genetic circuits,scaffolds
The lysine-specific demethylase1 (LSD1) in physiology and pathology (LSD1)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Physiology, Pathophysiology and Endocrinology
Countries involved: Germany
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-04-01
End date: 2018-03-31
Duration (months): 60.0
Total project cost (EUR): 2488800.0
EU funding (EUR): 2488800.0
Participants: 1
Project status: CLOSED

The identification of the first histone demethylase lysine-specific demethylase 1 (LSD1) established not only the concept of reversible histone methylation in epigenetic regulation but also translated this fundamentally novel biological observation into understanding the molecular mechanisms regulation stemness, differentiation, proliferation, and pathological growth. To unravel in an unbiased and comprehensive manner the biological function of LSD1 in physiology and pathology, we developed LSD1-deficient and LSD1-transgenic mouse models. LSD1-transgenic animals develop prostate tumours demonstrating that increased expression of LSD1 suffices for oncogenic growth in vivo. In addition, LSD1-transgenic animals exhibit a metabolic shift towards overt obesity in adulthood. LSD1-deficiency causes early embryonic lethality around day 7.5 of development. However, deletion of LSD1 is not essential for the development of the embryo proper until the onset of gastrulation, suggesting that the early embryonic lethality is caused by trophoblast defects. Indeed, our data demonstrate that LSD1 is crucial for maintaining trophoblast stem cells in their niche and required for the specification of trophoblast stem cell fate during initial steps of differentiation. To identify the underlying mechanisms that allow LSD1 to control a wide range of biological systems such as trophoblast stem cell fate in the early embryo, obesity, and prostate tumourigenesis in the adult, we propose to a) identify LSD1-associated protein complexes and b) LSD1 target genes establishing these phenotypes in the mouse. In addition, we shall uncover c) signalling pathways that modify LSD1 in these phenotypes allowing us to explore the therapeutic potential of targeting these signalling pathways.

Keywords: epigenetics,trophoblast stem cell
Islam in the Horn of Africa: A Comparative Literary Approach (ISLHORNAFR)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Cultures and cultural production
Countries involved: Denmark,Italy
Call:  (ERC-2012-ADG_20120411, 2012)
Start date: 2013-07-01
End date: 2018-12-31
Duration (months): 66.0
Total project cost (EUR): 1550200.0
EU funding (EUR): 1550200.0
Participants: 2
Project status: CLOSED

The study of Africa as a region "peripheral" to mainstream Islamic studies helps a deeper understanding of the cultural dynamics of Islam. While North African Islam has been subject to extensive research, the Muslim cultures of sub-Saharan Africa have received relatively little attention; most of it paid to West African regions. This project will contribute to both African and Islamic studies by producing for the first time a critical evaluation of textual witnesses of Islamic culture in the Horn of Africa (esp. Eritrea, Ethiopia, Djibouti, Somaliland) and therefore considerably contribute to the change in the state-of-the-art in both Islamic and African studies. The comparative study will be the first to assess simultaneously types and contents of texts, their transmission history, and the role they (as well as the respective authors and copyists) have played in the culture and identity formation in both the Horn of Africa and the “heartland” Islamic countries. Both Arabic texts as well as those written in local languages (using Arabic alphabet: ajami) will be considered, allowing an evaluation of linguistic and cultural influences. A reevaluation of the external Islamic sources dealing with these areas will complete the picture. Competences in philology, history, manuscript studies, linguistics and computer science will be merged in producing a Digital Research Environment for North-East African Islam. More than a corpus of centrally collected data, it will include images accompanied by searchable descriptive metadata, digital text editions, bibliography as well as an open access database for quantitative and qualitative comparative analysis of text and documentary corpora as well as their linguistic and graphic features will serve as a tool for the project and as a basis for future research. The research findings will provide a deeper understanding of Muslim thought and proselytism, and the effects Islam has had on society.

Keywords: islamic studies,arabic literature,ajami,manuscripts,literary history,horn of africa,ethiopia,eritrea,somalia
Deciphering the regulatory T cell repertoire: towards biomarkers and biotherapies for autoimmune diseases (TRIPOD)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Diagnostic tools, therapies and public health
Countries involved: France,Germany
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-05-01
End date: 2019-06-30
Duration (months): 74.0
Total project cost (EUR): 2500000.0
EU funding (EUR): 2500000.0
Participants: 2
Project status: CLOSED

The discovery of regulatory T cells (Tregs) is a breakthrough in immunology: it revolutionises our understanding of autoimmune disease (AID) pathophysiology and treatment opportunities. Treg numbers or function is defective in most mouse and human AIDs and their restoration induces clinical improvement, as we recently showed using low-dose IL-2 to induce Tregs in patients with AID. The TRiPoD project is based on 3 well supported assertions: - Tregs have huge therapeutic potential - Deep understanding of the Treg T cell receptor (TCR) repertoire is key to exploiting this potential - Deep sequencing technologies required for this purpose have come of age TRiPoD aims (i) to decipher the Treg repertoire against insulin and myelin at high resolution, (ii) to discover biomarkers for AIDs, and (iii) to develop therapies based on engineered Tregs. Deep sequencing of TCRs from insulin- and myelin-specific Tregs generated in vitro will identify dominant TCRs and antigen-specific Treg signatures. These will be analysed during thymocyte differentiation, at steady state and during disease progression, in mice and humans. Their potential as biomarkers (e.g. a Treg TCR specific for insulin for monitoring type 1 diabetes [T1D]) will be tested in experimental models and in clinical trials of IL-2 in T1D and multiple sclerosis (MS). We will also generate antigen-specific Tregs expressing the dominant TCRs and investigate their therapeutic properties. Ultimately, TRiPoD will contribute to a better understanding of the pathophysiology of T1D and MS, identify novel biomarkers for the follow-up of patients at high risk of, or with T1D or MS, and generate novel therapeutics for clinical development. More generally, our results and new approaches developed in TRiPoD should pioneer biomarker discovery and biotherapies in other immunopathologies.

Keywords: regulatory t cells,new generation sequencing,biomarkers,cell therapy,lentiviral vectors,autoimmune diseases
Development of Vascular-Disrupting Lymphocyte Therapy for Tumours (ANTIVESSEL-T-CELLS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Advanced grants
Action type: Support for frontier research (ERC)
Panel: Diagnostic tools, therapies and public health
Countries involved: Switzerland
Call:  (ERC-2012-ADG_20120314, 2012)
Start date: 2013-08-01
End date: 2018-07-31
Duration (months): 60.0
Total project cost (EUR): 2500000.0
EU funding (EUR): 2500000.0
Participants: 2
Project status: CLOSED

T cell engineering with chimeric antigen receptors has opened the door to effective immunotherapy. CARs are fusion genes encoding receptors whose extracellular domain comprises a single chain variable fragment (scFv) antibody that binds to a tumour surface epitope, while the intracellular domain comprises the signalling module of CD3ζ along with powerful costimulatory domains (e.g. CD28 and/or 4-1BB). CARs are a major breakthrough, since they allow bypassing HLA restrictions or loss, and they can incorporate potent costimulatory signals tailored to optimize T cell function. However, solid tumours present challenges, since they are often genetically unstable, and the tumour microenvironment impedes T cell function. The tumour vasculature is a much more stable and accessible target, and its disruption has catastrophic consequences for tumours. Nevertheless, the lack of affinity reagents has impeded progress in this area. The objectives of this proposal are to develop the first potent and safe tumour vascular-disrupting tumour immunotherapy using scFv’s and CARs uniquely available in my laboratory. I propose to use these innovative CARs to understand for the first time the molecular mechanisms underlying the interactions between anti-vascular CAR-T cells and tumour endothelium, and exploit them to maximize tumour vascular destruction. I also intend to employ innovative engineering approaches to minimize the chance of reactivity against normal vasculature. Lastly, I propose to manipulate the tumour damage mechanisms ensuing anti-vascular therapy, to maximize tumour rejection through immunomodulation. We are poised to elucidate critical interactions between tumour endothelium and anti-vascular T cells, and bring to bear cancer therapy of unparalleled power. The impact of this work could be transforming, given the applicability of tumour-vascular disruption across most common tumour types.

Keywords: cancer immunotherapy