Project acronym AIR-NB
Project Pre-natal exposure to urban AIR pollution and pre- and post-Natal Brain development
Researcher (PI) Jordi Sunyer
Host Institution (HI) FUNDACION PRIVADA INSTITUTO DE SALUD GLOBAL BARCELONA
Call Details Advanced Grant (AdG), LS7, ERC-2017-ADG
Summary 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.
Summary
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.
Max ERC Funding
2 499 992 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym DecodeDiabetes
Project Expanding the genetic etiological and diagnostic spectrum of monogenic diabetes mellitus
Researcher (PI) Jorge FERRER
Host Institution (HI) FUNDACIO CENTRE DE REGULACIO GENOMICA
Call Details Advanced Grant (AdG), LS4, ERC-2017-ADG
Summary Whole genome sequencing is quickly becoming a routine clinical instrument. However, our ability to decipher DNA variants is still largely limited to protein-coding exons, which comprise 1% of the genome. Most known Mendelian mutations are in exons, yet genetic testing still fails to show causal coding mutations in more than 50% of well-characterized Mendelian disorders. This defines a pressing need to interpret noncoding genome sequences, and to establish the role of noncoding mutations in Mendelian disease.
A recent case study harnessed whole genome sequencing, epigenomics, and functional genomics to show that mutations in an enhancer cause most cases of neonatal diabetes due to pancreas agenesis. This example raises major questions: (i) what is the overall impact of penetrant regulatory mutations in human diabetes? (ii) do regulatory mutations cause distinct forms of diabetes? (iii) more generally, can we develop a strategy to systematically tackle regulatory variation in Mendelian disease?
The current project will address these questions with unique resources. First, we have created epigenomic and functional perturbation resources to interpret the regulatory genome in embryonic pancreas and adult pancreatic islets. Second, we have collected an unprecedented international cohort of patients with a phenotype consistent with monogenic diabetes, yet lacking mutations in known gene culprits after genetic testing, and therefore with increased likelihood of harboring noncoding mutations. Third, we have developed a prototype platform to sequence regulatory mutations in a large number of patients.
These resources will be combined with innovative strategies to uncover causal enhancer mutations underlying Mendelian diabetes. If successful, this project will expand the diagnostic spectrum of diabetes, it will discover new genetic regulators of diabetes-relevant networks, and will provide a framework to understand regulatory variation in Mendelian disease.
Summary
Whole genome sequencing is quickly becoming a routine clinical instrument. However, our ability to decipher DNA variants is still largely limited to protein-coding exons, which comprise 1% of the genome. Most known Mendelian mutations are in exons, yet genetic testing still fails to show causal coding mutations in more than 50% of well-characterized Mendelian disorders. This defines a pressing need to interpret noncoding genome sequences, and to establish the role of noncoding mutations in Mendelian disease.
A recent case study harnessed whole genome sequencing, epigenomics, and functional genomics to show that mutations in an enhancer cause most cases of neonatal diabetes due to pancreas agenesis. This example raises major questions: (i) what is the overall impact of penetrant regulatory mutations in human diabetes? (ii) do regulatory mutations cause distinct forms of diabetes? (iii) more generally, can we develop a strategy to systematically tackle regulatory variation in Mendelian disease?
The current project will address these questions with unique resources. First, we have created epigenomic and functional perturbation resources to interpret the regulatory genome in embryonic pancreas and adult pancreatic islets. Second, we have collected an unprecedented international cohort of patients with a phenotype consistent with monogenic diabetes, yet lacking mutations in known gene culprits after genetic testing, and therefore with increased likelihood of harboring noncoding mutations. Third, we have developed a prototype platform to sequence regulatory mutations in a large number of patients.
These resources will be combined with innovative strategies to uncover causal enhancer mutations underlying Mendelian diabetes. If successful, this project will expand the diagnostic spectrum of diabetes, it will discover new genetic regulators of diabetes-relevant networks, and will provide a framework to understand regulatory variation in Mendelian disease.
Max ERC Funding
2 243 746 €
Duration
Start date: 2018-11-01, End date: 2023-10-31
Project acronym LIPOMET
Project Dietary Influences on Metastasis: How, When, and Why
Researcher (PI) Salvador Aznar Benitah
Host Institution (HI) FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA)
Call Details Advanced Grant (AdG), LS4, ERC-2017-ADG
Summary We have recently identified metastasis-initiating cells (MICs) in several types of tumors (Nature, 2017)1.
Intriguingly, MICs: (i) are exclusive in their ability to generate metastases when transplanted; (ii) express the
fatty acid channel CD36 and have a unique lipid metabolic signature; (iii) are exquisitely sensitive to the
levels of fat in circulation, thus providing a link between the predisposition of metastasis and dietary fat; (iv)
are highly sensitive to CD36 inhibition, which almost completely abolishes their metastatic potential.
We still do not know how MICs promote metastasis or how MICs are influenced by dietary fat. In
particular: (A) where are MICs located within the tumor, and does this location influence their behavior?
How and where do they attach and expand at metastatic sites? (B) Why are MICs so sensitive to specific
dietary lipids, and how do these lipids promote metastasis at the molecular and cellular levels? (C) Is the
prolonged consumption of a high-fat diet a risk factor for developing metastatic tumors? If so, what are the
underlying genetic and epigenetic causes for this effect? Can we revert these causes?
To answer these questions, we will combine state-of-the-art in vivo functional models of metastasis, with
quantitative metabolomics and proteomics, epigenetic and geographical position (3D) single-cell
transcriptomic studies, as well as integrative computational analyses, using preclinical models and patientderived
carcinomas of melanoma, oral cancer and breast cancer.
We expect our project to provide fundamental insights into the mechanisms of metastasis, and how they are
influenced by diet. This is highly relevant as 1) large quantities of fatty acids are typically consumed in
Western diets; and 2) metastasis is the leading cause of cancer-related deaths. We also tackle a timely
medical unmet need by exploring the therapeutic anti-metastatic potential of targeting fatty acid metabolism
in cancer patients.
Summary
We have recently identified metastasis-initiating cells (MICs) in several types of tumors (Nature, 2017)1.
Intriguingly, MICs: (i) are exclusive in their ability to generate metastases when transplanted; (ii) express the
fatty acid channel CD36 and have a unique lipid metabolic signature; (iii) are exquisitely sensitive to the
levels of fat in circulation, thus providing a link between the predisposition of metastasis and dietary fat; (iv)
are highly sensitive to CD36 inhibition, which almost completely abolishes their metastatic potential.
We still do not know how MICs promote metastasis or how MICs are influenced by dietary fat. In
particular: (A) where are MICs located within the tumor, and does this location influence their behavior?
How and where do they attach and expand at metastatic sites? (B) Why are MICs so sensitive to specific
dietary lipids, and how do these lipids promote metastasis at the molecular and cellular levels? (C) Is the
prolonged consumption of a high-fat diet a risk factor for developing metastatic tumors? If so, what are the
underlying genetic and epigenetic causes for this effect? Can we revert these causes?
To answer these questions, we will combine state-of-the-art in vivo functional models of metastasis, with
quantitative metabolomics and proteomics, epigenetic and geographical position (3D) single-cell
transcriptomic studies, as well as integrative computational analyses, using preclinical models and patientderived
carcinomas of melanoma, oral cancer and breast cancer.
We expect our project to provide fundamental insights into the mechanisms of metastasis, and how they are
influenced by diet. This is highly relevant as 1) large quantities of fatty acids are typically consumed in
Western diets; and 2) metastasis is the leading cause of cancer-related deaths. We also tackle a timely
medical unmet need by exploring the therapeutic anti-metastatic potential of targeting fatty acid metabolism
in cancer patients.
Max ERC Funding
2 370 625 €
Duration
Start date: 2018-08-01, End date: 2023-07-31
Project acronym NANO-MEMEC
Project Membrane-based nano-mechanobiology: Role of mechanical forces in remodelling the spatiotemporal nanoarchitecture of the plasma membrane
Researcher (PI) María Filomena García Parajo
Host Institution (HI) FUNDACIO INSTITUT DE CIENCIES FOTONIQUES
Call Details Advanced Grant (AdG), LS1, ERC-2017-ADG
Summary Through evolution, cells have developed the exquisite ability to sense, transduce and integrate mechanical and biochemical signals (i.e. mechanobiology) to generate appropriate responses. These key events are rooted at the molecular and nanoscale levels, a size regime difficult to access, hindering our progress towards mechanistic understanding of mechanobiology. Recent evidence from my Lab (and others) shows that the lateral nanoscale organisation of mechanosensitive membrane receptors and signalling molecules is crucial for cell function. Yet, current models of mechanosensing are based on force-induced molecular conformations, completely overlooking the chief role of mechanical forces on the nanoscale spatiotemporal organisation of the plasma membrane.
The GOAL of NANO-MEMEC is to provide mechanistic understanding on the role of mechanical stimuli in the spatiotemporal nanoarchitecture of adhesion signalling platforms at the cell membrane. To overcome the technical challenges of probing these processes at the relevant spatiotemporal scales, I will exploit cuttingedge biophysical tools exclusively developed in my Lab that combine super-resolution optical nanoscopy and single molecule dynamics in conjunction with simultaneous mechanical stimulation of living cells. Using this integrated approach, I will: First: dissect mechanical and biochemical coupling of membrane mechanosensing at the nanoscale. Second: visualise the coordinated recruitment of integrin-associated signalling proteins in response to force, i.e., mechanotransduction. Third: test how force-induced spatiotemporal membrane remodelling influences the migratory capacity of immune cells, i.e., mechanoresponse. NANO-MEMEC conveys a new fundamental concept to the field of mechanobiology: the roles of mechanical stimuli in the
dynamic remodelling of membrane nanocompartments, modulating signal transduction and ultimately affecting cell response, opening new-fangled research avenues in the years to come.
Summary
Through evolution, cells have developed the exquisite ability to sense, transduce and integrate mechanical and biochemical signals (i.e. mechanobiology) to generate appropriate responses. These key events are rooted at the molecular and nanoscale levels, a size regime difficult to access, hindering our progress towards mechanistic understanding of mechanobiology. Recent evidence from my Lab (and others) shows that the lateral nanoscale organisation of mechanosensitive membrane receptors and signalling molecules is crucial for cell function. Yet, current models of mechanosensing are based on force-induced molecular conformations, completely overlooking the chief role of mechanical forces on the nanoscale spatiotemporal organisation of the plasma membrane.
The GOAL of NANO-MEMEC is to provide mechanistic understanding on the role of mechanical stimuli in the spatiotemporal nanoarchitecture of adhesion signalling platforms at the cell membrane. To overcome the technical challenges of probing these processes at the relevant spatiotemporal scales, I will exploit cuttingedge biophysical tools exclusively developed in my Lab that combine super-resolution optical nanoscopy and single molecule dynamics in conjunction with simultaneous mechanical stimulation of living cells. Using this integrated approach, I will: First: dissect mechanical and biochemical coupling of membrane mechanosensing at the nanoscale. Second: visualise the coordinated recruitment of integrin-associated signalling proteins in response to force, i.e., mechanotransduction. Third: test how force-induced spatiotemporal membrane remodelling influences the migratory capacity of immune cells, i.e., mechanoresponse. NANO-MEMEC conveys a new fundamental concept to the field of mechanobiology: the roles of mechanical stimuli in the
dynamic remodelling of membrane nanocompartments, modulating signal transduction and ultimately affecting cell response, opening new-fangled research avenues in the years to come.
Max ERC Funding
2 212 063 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
