ERC FUNDED PROJECTS

Air pollution is the main urban-related environmental hazard. It appears to affect brain development, although current evidence is inadequate given the lack of studies during the most vulnerable stages of brain development and the lack of brain anatomical structure and regional connectivity data underlying these effects. Of particular interest is the prenatal period, when brain structures are forming and growing, and when the effect of in utero exposure to environmental factors may cause permanent brain injury. I and others have conducted studies focused on effects during school age which could be less profound. I postulate that: pre-natal exposure to urban air pollution during pregnancy impairs foetal and postnatal brain development, mainly by affecting myelination; these effects are at least partially mediated by translocation of airborne particulate matter to the placenta and by placental dysfunction; and prenatal exposure to air pollution impairs post-natal brain development independently of urban context and post-natal exposure to air pollution. I aim to evaluate the effect of pre-natal exposure to urban air pollution on pre- and post-natal brain structure and function by following 900 pregnant women and their neonates with contrasting levels of pre-natal exposure to air pollutants by: i) establishing a new pregnancy cohort and evaluating brain imaging (pre-natal and neo-natal brain structure, connectivity and function), and post-natal motor and cognitive development; ii) measuring total personal exposure and inhaled dose of air pollutants during specific time-windows of gestation, noise, paternal stress and other stressors, using personal samplers and sensors; iii) detecting nanoparticles in placenta and its vascular function; iv) modelling mathematical causality and mediation, including a replication study in an external cohort. The expected results will create an impulse to implement policy interventions that genuinely protect the health of urban citizens.

2 499 992 €

Start date: 2018-09-01, End date: 2023-08-31

The long-term goal of this proposal is to explore a novel immune pathway that involves an unexpected interplay between marginal zone (MZ) B cells and neutrophils. MZ B cells are strategically positioned at the interface between the immune system and the circulation and rapidly produce protective antibodies to blood-borne pathogens through a T cell-independent pathway that remains poorly understood. We recently found that the human spleen contains a novel subset of B cell helper neutrophils (NBH cells) with a phenotype and gene expression profile distinct from those of conventional circulating neutrophils (NC cells). In this proposal, we hypothesize that NC cells undergo splenic reprogramming into NBH cells through an IL-10-dependent pathway involving perifollicular sinusoidal endothelial cells. We contend that these unique endothelial cells release NC cell-attracting chemokines and IL-10 upon sensing blood-borne bacteria through Toll-like receptors. We also argue that IL-10 from sinusoidal endothelial cells stimulates NC cells to differentiate into NBH cells equipped with powerful MZ B cell-stimulating activity. The following three aims will be pursued. Aim 1 is to determine the mechanisms by which splenic sinusoidal endothelial cells induce reprogramming of NC cells into NBH cells upon sensing bacteria through Toll-like receptors. Aim 2 is to elucidate the mechanisms by which NBH cells induce IgM production, IgG and IgA class switching, and plasma cell differentiation in MZ B cells. Aim 3 is to evaluate the mechanisms by which NBH cells induce V(D)J gene somatic hypermutation and high-affinity antibody production in MZ B cells. These studies will uncover previously unknown facets of the immunological function of neutrophils by taking advantage of unique cells and tissues from patients with rare primary immunodeficiencies and by making use of selected mouse models. Results from these studies may also lead to the identification of novel vaccine strategies.

2 214 035 €

Start date: 2012-04-01, End date: 2017-09-30

Membranes of eukaryotic cells organize signal transduction proteins into microdomains or lipid rafts whose integrity is essential for numerous cellular processes. Lipid rafts has been considered a fundamental step to define the cellular complexity of eukaryotes, assuming that bacteria do not require such a sophisticated organization of their signaling networks. However, I have discovered that bacteria organize many signaling pathways in membrane microdomains similar to the eukaryotic lipid rafts. Perturbation of bacterial lipid rafts leads to a potent and simultaneous impairment of all raft-harbored signaling pathways. Consequently, the disassembly of lipid rafts in pathogens like Staphylococcus aureus generates a simultaneous inhibition of numerous infection-related processes that can be further explored to control bacterial infections. This unexpected sophistication in membrane organization is unprecedented in bacteria and hence, this proposal will explore the molecular basis of the assembly of bacterial lipid rafts and their role in the infection-related processes. These questions will be addressed in three main goals: First, I will elucidate the molecular components and the mechanism of assembly of bacterial lipid rafts using S. aureus as model organism. Second, I will dissect the molecular basis that links the functionality of the infection-related processes to the integrity of bacterial lipid rafts. Third, my collection of anti-raft small molecules that are able to disrupt lipid rafts will be tested as antimicrobial agents to prevent hospital-acquired infections, abrogate pre-existing infections and develop bacteria-free materials that can be used in clinical settings. I will use a number of molecular approaches in combination with cutting-edge techniques in flow cytometry, cell-imaging and transcriptomics to clarify the architecture and functionality of lipid rafts and demonstrate the feasibility of targeting lipid a new strategy for anti-microbial therapy.

1 493 126 €

Start date: 2014-03-01, End date: 2019-02-28

Over the past 20 years cosmology has made the transition to a precision science: the standard cosmological model has been established and its parameters are now measured with unprecedented precision. But precision is not enough: accuracy is also crucial. Accuracy accounts for systematic errors which can be both on the observational and on the theory/modelling side (and everywhere in between). While there is a well-defined and developed framework for treating statistical errors, there is no established approach for systematic errors. The next decade will see the era of large surveys; a large coordinated effort of the scientific community in the field is on-going to map the cosmos producing an exponentially growing amount of data. This will shrink the statistical errors, making mitigation and control of systematics of the utmost importance. While there are isolated and targeted efforts to quantify systematic errors and propagate them through all the way to the final results, there is no well-established, self-consistent methodology. To go beyond precision cosmology and reap the benefits of the forthcoming observational program, a systematic approach to systematics is needed. Systematics should be interpreted in the most general sense as shifts between the recovered measured values and true values of physical quantities. I propose to develop a comprehensive approach to tackle systematic errors with the goal to uncover and quantify otherwise unknown differences between the interpretation of a measurement and reality. This will require to fully develop, combine and systematize all approaches proposed so far (many pioneered by the PI), develop new ones to fill the gaps, study and explore their interplay and finally test and validate the procedure. Beyond Precision Cosmology: Dealing with Systematic Errors (BePreSysE) will develop a framework to deal with systematics in forthcoming Cosmological surveys which, could, in principle, be applied beyond Cosmology.

1 835 220 €

Start date: 2017-06-01, End date: 2022-05-31