Data-Gouv-ML/pcri-informations-sur-les-projets-laureats huggingface dataset:
Metabolic oscillations and the 24 hour (circadian) clockwork (METACLOCK)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Molecular and Structural Biology and Biochemistry
Countries involved: United Kingdom
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-10-01
End date: 2016-09-30
Duration (months): 60.0
Total project cost (EUR): 1998056.0
EU funding (EUR): 1998056.0
Participants: 1
Project status: CLOSED

We live in a "24 hour" culture, with transatlantic air travel and shift-work being part of normal life for many people. These types of desynchronisations (e.g. “jet-lag”) disrupt our daily physiology and are increasingly being linked to diseases such as diabetes, obesity and cancer. Daily rhythms are also impaired in the elderly, and in patients with common neurodegenerative conditions such as Alzheimer-type and fronto-temporal dementias, meaning that clock disruption is widespread in modern society. We know that every cell in the body has its own molecular clock, allowing it to coordinate its daily activities accurately, just as we would use a clock in our daily lives. Our work has uncovered novel mechanisms about how this works and how this fundamental timing system may have evolved in primitive single-celled organisms. By understanding these basic cellular mechanisms in greater detail, we anticipate that we will gain insights into how metabolic oscillations in each cell contribute to normal physiology and therefore disease.

Keywords: circadian clock peroxiredoxin redox mitochondria
The nuclear pore connection: adaptor complexes bridging genome regulation and nuclear transport (NPC GENEXPRESS)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Molecular and Structural Biology and Biochemistry
Countries involved: Austria
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-11-01
End date: 2016-10-31
Duration (months): 60.0
Total project cost (EUR): 1481556.0
EU funding (EUR): 1481556.0
Participants: 1
Project status: CLOSED

Nuclear pore complexes (NPCs) form macromolecular assemblies in the nuclear envelope and mediate bidirectional cargo movement between the nucleus and cytoplasm. Recent evidence suggests that NPCs are not merely transport channels but act as gene regulators. Studies in yeast demonstrate that inducible genes can reposition from the nuclear interior to the nuclear periphery upon activation. At the periphery activated genes engage in physical contacts with nuclear pores. Targeting and tethering of genes to nuclear pores involves multifunctional adaptor complexes, which are thought to couple chromatin modification, transcription and mRNA export. Knowledge of the structure, dynamics and evolution of these adaptor complexes is key to understanding how NPCs control nuclear gene positioning and gene expression. I propose to systematically dissect the architecture and function of NPC-associated adaptor complexes. Our studies will be a unique combination of biochemical and structural approaches in three different model organisms. I anticipate, that this line of research will create a powerful basis to address a number of key questions in the field.

Keywords: nuclear pore complex,nuclear architecture,gene expression,chromatin,ubiquitin signaling,mrna export
Systems Genetics of Heritable variaTions (SIGHT)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Genetics,Genomics,Bioinformatics and Systems Biology
Countries involved: France
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-02-01
End date: 2017-01-31
Duration (months): 60.0
Total project cost (EUR): 1499660.0
EU funding (EUR): 1499660.0
Participants: 1
Project status: CLOSED

The complexity by which genotypes modulate phenotypic variation has been a major obstacle in understanding the basis of inter-individual differences. In the particular case of disease susceptibility, enormous efforts have been conducted among large consortia of quantitative geneticists, and a recent wealth of results showed both victories and frustrations. Victories because many genetic factors could successfully be linked to diabetes, heart failure, cancer, infectivity, and many other common diseases. Frustrations as it is becoming more and more apparent that genetic dissections are far from completion, with many unsolved questions especially regarding gene x environment interactions and incomplete penetrance. In this context, I propose to revisit the molecular basis of phenotypic diversity by addressing fundamental questions in a simple and powerful model organism: the yeast S. cerevisiae. Combining experimental biology and bioinformatics into a ‘systems’ approach, I propose 1) To reconsider our current view of genetic determinism. By examining the effect of genetic variation on single-cells, we will visualise how they shape probability laws underlying phenotypic outcomes. This will prepare us to the upcoming era of generalized single-cell analysis. 2) To investigate how chromatin epigenotypes affect phenotypic variations. We will characterize nucleosomal epi-polymorphisms and study their impact on transcriptional and phenotypic responses to environmental changes. This will establish whether and how individual epigenomes should be considered when planning trait dissections. This ambitious project is grounded on solid preliminary results and can be achieved thanks to my dual expertise in numerical science and experimental genetics. The questions addressed are fundamental for our understanding of living systems and the innovative methodology will help us integrate upcoming technologies into the construction of personalized medicine.

Keywords: genetical genomics,yeast genetics,statistical genomics,bioinformatics
p53 as a New Mediator of Energy Balance in the Brain (OBESITY53)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Physiology, Pathophysiology and Endocrinology
Countries involved: Spain
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-12-01
End date: 2017-05-31
Duration (months): 66.0
Total project cost (EUR): 1477680.0
EU funding (EUR): 1477680.0
Participants: 1
Project status: CLOSED

p53 is a transcriptional factor modulating numerous biological actions. Although it is best known for its role in cancer development, it is now evident that it is implicated in metabolism. More specifically, p53 modulates energy metabolism and homeostasis through their effects on adipocyte development and function. However, nothing is known about the potential metabolic function of p53 in the central nervous system. Neuronal networks within the central nervous system play a crucial role in the regulation of food intake, body weight, and glucose homeostasis, so the main objective of this project will be to evaluate the potential of brain p53 as anti-obesity and/or anti-diabetic drug candidate. Our project will dissect precisely which specific components of energy balance are altered after central disruption or rescue of p53 signalling in selective neuronal populations, as well as the molecular pathways mediating these actions. More precisely, we will disrupt the central p53 signalling specifically in hypothalamic POMC and AgRP neurons, which are crucial for energy and glucose homeostasis. We will also generate and characterize mice lacking p53 in dopamine neurons that are essential for mechanisms related with the reward of food. Once we know which specific areas are crucial for the central actions of p53, we will complete the experiments rescuing p53 expression in selective neuronal populations (POMC, AgRP or dopamine neurons) of p53 null mice. We will also investigate the interaction between p53 with leptin and ghrelin, likely the two more important hormones in the regulation of energy balance, which act through homeostatic and hedonic mechanisms. Understanding the precise role and mechanisms regulated by central p53 on energy balance may open new avenues for the identification of potential anti-obesity drug targets directed towards specific molecular pathways.

Keywords: obesity,central nervous system
Childhood body size, growth and pubertal timing and the risk of cancer in adulthood (CHILDGROWTH2CANCER)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Diagnostic tools, therapies and public health
Countries involved: Denmark
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-02-01
End date: 2017-01-31
Duration (months): 60.0
Total project cost (EUR): 1199998.16
EU funding (EUR): 1199998.16
Participants: 1
Project status: CLOSED

The goal of the proposed research is to examine how the independent and combined effects of childhood adiposity (assessed by body mass index [BMI]; kg/m2) height, change in BMI and height, and pubertal timing from the ages of 7 to 13 years are associated with the risk of cancer incidence in adulthood. Greater body size (adipose tissue and different types of lean tissue) reflecting past or ongoing growth may increase the risk of cancer in individuals as greater numbers of proliferating cells increase the risk that mutations leading to the subsequent development of cancer occur. As childhood is a period of growth, it is plausible that it is of particular relevance for the early establishment of the risk of cancer. Data from the Copenhagen School Health Records Register, which is based on a population of schoolchildren born between 1930-1983 and contains computerised weight and height measurements on >350.000 boys and girls in the capital city of Denmark, as well as data from other cohorts will be used. Survival analysis techniques and the newly developed Dynamic Path Analysis model will be used to examine how body size (BMI and height) at each age from 7 to 13 years as well as change in body size during this period is associated with the risk of multiple forms of cancer in adulthood with a simultaneous exploration of the effects of birth weight and pubertal timing. Additionally, potential effects of childhood and adult health and social circumstances will be investigated in sub-cohorts with this information available. Results from this research will demonstrate if childhood is a critical period for the establishment of the risk for cancer in adulthood and will lead into mechanistic explorations of the associations at the biological level, investigations into associations between childhood body size and mortality and contribute to developing improved definitions of childhood overweight and obesity that are based upon long-term health outcomes.

Keywords: adulthood,cancer,childhood,follow-up study,growth,height,obesity
Engineering Vascularized Tissues (ENGVASC)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Diagnostic tools, therapies and public health
Countries involved: Israel
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-10-01
End date: 2017-09-30
Duration (months): 60.0
Total project cost (EUR): 1500000.0
EU funding (EUR): 1500000.0
Participants: 1
Project status: CLOSED

Vascularization, the process in which new blood vessels assemble, is fundamental to tissue vitality. Vessel network assembly within 3D tissues can be induced in-vitro by means of multicellular culturing of endothelial cells (EC), fibroblasts and cells specific to the tissue of interest. This approach supports formation of endothelial vessels and promotes EC and tissue-specific cell interactions. Such EC-dependent tube-like openings may also form the basis for improved media penetration to the inner regions of thick 3D constructs, allowing for enhanced construct survival and for effective engineering of large complex tissues in the lab. Moreover, our own breakthrough results describe the beneficial impact of in vitro prevascularization of engineered muscle tissue on its survival and vascularization upon implantation. These studies have also demonstrated that implanted vascular networks of in vitro engineered constructs, can anastomose with host vasculature and form functional blood vessels in vivo. However, the mechanisms underlying enhanced vascularization of endothelialized engineered constructs and implant-host vessel integration remain unclear. In this proposal, our research objectives are (1) to uncover the mechanisms governing in vitro vessel network formation in engineered 3D tissues and (2) to elucidate the process of graft-host vessel network integration and implant vessel-stimulated promotion of neovascularization in vivo. In addition, the impact of construct prevascularization on implant survival and function will be explored in animal disease models. While there are still many challenges ahead, should we succeed, our research could lay the foundation for significantly enhanced tissue construct vascularization procedures and for their application in regenerative medicine. In addition, it may provide alternative models for studying the vascularization processes in embryogenesis and disease.

Keywords: tissue engineering,vascularization,biomaterials
Cytoskeletal force generation and force transduction of migrating leukocytes (LEUKOCYTEFORCES)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Cellular and Developmental Biology
Countries involved: Austria
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-04-01
End date: 2017-03-31
Duration (months): 60.0
Total project cost (EUR): 1458125.0
EU funding (EUR): 1458125.0
Participants: 1
Project status: CLOSED

Cell migration is a universal feature of all metazoan life and crucially involved in most developmental, homeostatic and pathological processes. Most efforts to understand its molecular and mechanical aspects were focused on the “haptokinetic” paradigm. Here cells generate traction by coupling the protrusive and contractile forces of the actomyosin cytoskeleton via transmembrane receptors to the extracellular environment. Our recent work demonstrated that leukocytes, the class of animal cells that migrates with highest speed and efficiency, violate this paradigm. Once embedded in physiological three-dimensional matrices they instantaneously shift between adhesive and non-adhesive modes to transduce force. This proposal suggests a combined cell biological and biophysical approach to elucidate the molecular and mechanical principles underlying such plasticity. We will focus on the machinery most proximate to force generation and use genetics and pharmacology to characterize how nucleation, elongation, depolymerization and crosslinking of actin filaments act in leukocytes migrating through environments of varying geometry and adhesive properties (Postdoc 1). Mechanical manipulations in conjunction with high resolution monitoring of substrate deformations will reveal how cytoskeletal force is transduced to the extracellular environment (Postdoc 2). In a technical support project (Technician) we will develop a cell-system with optimized access to stable genetic manipulations. Technically, these questions will be addressed by employing advanced live cell fluorescence imaging in combination with artificial environments engineered using microfluidics and substrate micropatterning. Importantly, findings will ultimately be challenged in living tissues. This multidisciplinary approach will generate an integrated view of locomotion-plasticity that will not only impact basic cell biology and immunology but also developmental and cancer biology.

Keywords: cell migration,leukocyte,cytoskeletal dynamics,actin,force transduction,adhesion
A cross-species neurogenomics approach to anxiety (GENANX)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Genetics,Genomics,Bioinformatics and Systems Biology
Countries involved: Finland
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-02-01
End date: 2017-07-31
Duration (months): 66.0
Total project cost (EUR): 1499863.0
EU funding (EUR): 1499863.0
Participants: 1
Project status: CLOSED

My goal is to identify novel genetic factors that regulate normal and pathological anxiety. Anxiety disorders are complex diseases with genetic and environmental susceptibility factors. Stressful life events, especially in childhood are well-known risk factors for anxiety disorders. We have previously used inbred mouse strains to identify genes underlying innate anxiety. Here I propose a new approach using a mouse model of anxiety induced by social stress to identify gene regulatory networks, to show the causality of the selected networks in vivo, and to investigate involvement of these networks in the genetic predisposition to human anxiety disorders. Gene regulatory networks will be identified by using massively parallel sequencing methods (i.e. miRNA-seq and mRNA-seq). We will generate from four brain regions known to regulate anxiety a complete gene and miRNA expression atlas, which is used to identify genes, transcripts, miRNAs and isomiRs differentially expressed between anxious and control animals. Pathway and network analysis tools are employed to identify molecular pathways affected by induced anxiety. Datasets consisting of different levels of data from individual brain regions will then be integrated in light of existing molecular and anatomical information to construct draft network models that will be curated, filtered and enhanced. On the basis of these models, we will generate specific hypotheses that are tested in vivo in mice to show the causality of the most interesting networks. To identify the networks important for human anxiety disorders, we have access to a unique population-based cohort from Finland characterized for anxiety disorders. Candidate genes and miRNAs from selected networks are tested in a genetic association analysis. This multidisciplinary project will increase understanding of the genetic and neurobiological basis of anxiety in mouse and human, and has potential to provide targets for the development of improved anxiolytics.

Keywords: anxiety disorders,anxiety-like behavior,psycosocial stress,gene expression,microrna expression,lentivirus-mediated gene transfer,genetic association analysis
Evolution of gene mobility: how mobile elements shape the function and sociality of microbial communities (EVOMOBILOME)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Evolutionary, population and environmental biology
Countries involved: France
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2012-07-01
End date: 2017-12-31
Duration (months): 66.0
Total project cost (EUR): 1298925.0
EU funding (EUR): 1298925.0
Participants: 1
Project status: CLOSED

Prokaryotes evolve rapidly new functionalities by horizontal gene transfer delivered by mobile genetic elements (MGE). MGE increase relatedness between individuals and thereby might also promote the establishment of microbial social networks. Many studies have detailed the dynamics of specific systems in specific MGE. Yet, how MGE key and accessory functions evolve as a whole at the face of social dilemmas arising in microbial communities is largely ignored. Here, I aim at an integrative identification and analysis of self-mobilizable elements to unravel an evolutionary framework of MGE contributions to prokaryotic evolution. We will use sequence similarity, phylogeny and population genetics techniques to detail how elements propagate and are maintained in populations. We will investigate how accessory functions work together in relation to interactions between MGE and of MGE with the host. We will then quantify the long-term impact of MGE to the gene repertoires of prokaryotes by analysis of the patterns of their degradation and/or domestication using regulatory networks and population genetics. The analysis of secretion systems and effectors in mobile elements will enlighten the role of gene mobility in promoting social behaviours thorugh production of public goods. The previous results will then be used to query metagenomics datasets about the roles of gene mobility and secretion in the social evolution of natural microbial populations. This work will pioneer the application of theoretical works in population genetics and social evolution to the study of natural microbial communities by way of evolutionary genomics. Its integrative outlook will also provide essential breakthroughs in the understanding of the evolutionary history of mechanisms of gene mobility, e.g. conjugation. Finally, this project will pinpoint how manipulation of MGE might allows control of virulence, antibiotic resistance and other phenomena related with microbial social interactions.

Keywords: mobile genetic elements,horizontal transfer,secretion,conjugation,transduction.
Protein damage control: regulation of toxic protein aggregation in aging-associated neurodegenerative diseases (PDCONTROL)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Cellular and Developmental Biology
Countries involved: Netherlands
Call:  (ERC-2011-StG_20101109, 2011)
Start date: 2011-12-01
End date: 2016-11-30
Duration (months): 60.0
Total project cost (EUR): 1450249.0
EU funding (EUR): 1450249.0
Participants: 1
Project status: CLOSED

The worldwide aging population will lead to a dramatic increase in the number of people with Alzheimer’s disease and other incurable age-related neurodegenerative diseases over the next few decades. By 2050 over 115 million are expected to suffer from these devastating diseases. The major pathological hallmark of these disorders is the accumulation of aggregation-prone disease proteins in aggregates in the brain. To understand the disease mechanisms and to identify targets for treatment, I aim to uncover the cellular pathways that regulate disease-protein toxicity and aggregation (proteotoxicity). Opening up such exciting new avenues for research is our recent identification of a modifier of aggregation, which we named MOAG-4, as a general regulator of age-related proteotoxicity in worm (C. elegans) models for neurodegenerative diseases. MOAG-4 and its human counterpart SERF act independently of classical pathways that degrade proteins or prevent their aggregation, but their molecular role remains to be determined. I hypothesize that MOAG-4/SERF represents a new regulatory pathway of age-related proteotoxicity in neurodegenerative diseases. With an ERC starting grant, I will uncover the pathway in which MOAG-4/SERF is operating, establish the mechanism by which the pathway regulates proteotoxicity, establish the evolutionarily conservation of the pathway in human cells, and establish its potential as a therapeutic target in patient-derived cells. By combining the power of C. elegans genetics with the development of cell-biological tools to visualize and monitor aggregation and toxicity in living and aging worms and in patient-derived cells, we will be at the forefront of providing new insights into disease-mechanisms. Our discoveries will offer new starting points for research and for the development of therapeutic interventions in the early molecular events of aging-associated neurodegenerative diseases.

Keywords: c. elegans,proteotoxicity,regulators of protein aggregation,aggregation-prone proteins,protein quality control,huntingtin,alpha-synuclein,amyloid beta