Project acronym BREATHE
Project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Researcher (PI) Jordi Sunyer Deu
Host Institution (HI) FUNDACION PRIVADA INSTITUTO DE SALUD GLOBAL BARCELONA
Call Details Advanced Grant (AdG), LS7, ERC-2010-AdG_20100317
Summary Traffic-related air pollution is an important environmental problem that may affect neurodevelopment. Ultrafine particles (UFP) translocate to the brains of experimental animals resulting in local proinflammatory overexpression. As the basic elements for thinking are acquired by developing brains during infancy and childhood, susceptibility may be elevated in early life.
We postulate that traffic-related air pollution (particularly UFPs and metals/hydrocarbons content) impairs neurodevelopment in part via effects on frontal lobe maturation, likely increasing attention-deficit/hyperactivity disorder (ADHD). BREATHE objectives are to develop valid methods to measure children's personal UFP exposure and to develop valid neuroimaging methods to assess correlations between neurobehavior, neurostructural alterations and particle deposition in order to reveal how traffic pollution affects children¿s exposure to key contaminants and brain development, and identify susceptible subgroups.
We have conducted general population birth cohort studies providing preliminary evidence of residential air pollution effects on prenatal growth and mental development.
We aim to demonstrate short and long-term effects on neurodevelopment using innovative epidemiological methods interfaced with environmental chemistry and neuroimaging following 4000 children from 40 schools with contrasting high/low traffic exposure in six linked components involving: repeated psychometric tests, UFP exposure assessment using personal, school and home measurements, gene-environment interactions on inflammation, detoxification pathways and ADHD genome-wide-associated genes, neuroimaging (magnetic resonance imaging/spectroscopy) in ADHD/non-ADHD children, integrative causal modeling using mathematics, and replication in 2900 children with neurodevelopment followed from pregnancy.
We believe the expected results will have worldwide global planning and policy implications.
Summary
Traffic-related air pollution is an important environmental problem that may affect neurodevelopment. Ultrafine particles (UFP) translocate to the brains of experimental animals resulting in local proinflammatory overexpression. As the basic elements for thinking are acquired by developing brains during infancy and childhood, susceptibility may be elevated in early life.
We postulate that traffic-related air pollution (particularly UFPs and metals/hydrocarbons content) impairs neurodevelopment in part via effects on frontal lobe maturation, likely increasing attention-deficit/hyperactivity disorder (ADHD). BREATHE objectives are to develop valid methods to measure children's personal UFP exposure and to develop valid neuroimaging methods to assess correlations between neurobehavior, neurostructural alterations and particle deposition in order to reveal how traffic pollution affects children¿s exposure to key contaminants and brain development, and identify susceptible subgroups.
We have conducted general population birth cohort studies providing preliminary evidence of residential air pollution effects on prenatal growth and mental development.
We aim to demonstrate short and long-term effects on neurodevelopment using innovative epidemiological methods interfaced with environmental chemistry and neuroimaging following 4000 children from 40 schools with contrasting high/low traffic exposure in six linked components involving: repeated psychometric tests, UFP exposure assessment using personal, school and home measurements, gene-environment interactions on inflammation, detoxification pathways and ADHD genome-wide-associated genes, neuroimaging (magnetic resonance imaging/spectroscopy) in ADHD/non-ADHD children, integrative causal modeling using mathematics, and replication in 2900 children with neurodevelopment followed from pregnancy.
We believe the expected results will have worldwide global planning and policy implications.
Max ERC Funding
2 499 230 €
Duration
Start date: 2011-08-01, End date: 2016-07-31
Project acronym CBSCS
Project Physiology of the adult carotid body stem cell niche
Researcher (PI) Ricardo Pardal
Host Institution (HI) UNIVERSIDAD DE SEVILLA
Call Details Starting Grant (StG), LS3, ERC-2010-StG_20091118
Summary The discovery of adult neural stem cells (NSCs) has broaden our view of the physiological plasticity of the nervous system,
and has opened new perspectives on the possibility of tissue regeneration and repair in the brain. NSCs reside in specialized
niches in the adult mammalian nervous system, where they are exposed to specific paracrine signals regulating their
behavior. These neural progenitors are generally in a quiescent state within their niche, and they activate their proliferation
depending on tissue regenerative and growth needs. Understanding the mechanisms by which NSCs enter and exit the
quiescent state is crucial for the comprehension of the physiology of the adult nervous system. In this project we will study
the behavior of a specific subpopulation of adult neural stem cells recently described by our group in the carotid body (CB).
This small organ constitutes the most important chemosensor of the peripheral nervous system and has neuronal glomus
cells responsible for the chemosensing, and glia-like sustentacular cells which were thought to have just a supportive role.
We recently described that these sustentacular cells are dormant stem cells able to activate their proliferation in response to a
physiological stimulus like hypoxia, and to differentiate into new glomus cells necessary for the adaptation of the organ.
Due to our precise experimental control of the activation and deactivation of the CB neurogenic niche, we believe the CB is
an ideal model to study fundamental questions about adult neural stem cell physiology and the interaction with the niche. We
propose to study the cellular and molecular mechanisms by which these carotid body stem cells enter and exit the quiescent
state, which will help us understand the physiology of adult neurogenic niches. Likewise, understanding this neurogenic
process will improve the efficacy of using glomus cells for cell therapy against neurological disease, and might help us
understand some neural tumors.
Summary
The discovery of adult neural stem cells (NSCs) has broaden our view of the physiological plasticity of the nervous system,
and has opened new perspectives on the possibility of tissue regeneration and repair in the brain. NSCs reside in specialized
niches in the adult mammalian nervous system, where they are exposed to specific paracrine signals regulating their
behavior. These neural progenitors are generally in a quiescent state within their niche, and they activate their proliferation
depending on tissue regenerative and growth needs. Understanding the mechanisms by which NSCs enter and exit the
quiescent state is crucial for the comprehension of the physiology of the adult nervous system. In this project we will study
the behavior of a specific subpopulation of adult neural stem cells recently described by our group in the carotid body (CB).
This small organ constitutes the most important chemosensor of the peripheral nervous system and has neuronal glomus
cells responsible for the chemosensing, and glia-like sustentacular cells which were thought to have just a supportive role.
We recently described that these sustentacular cells are dormant stem cells able to activate their proliferation in response to a
physiological stimulus like hypoxia, and to differentiate into new glomus cells necessary for the adaptation of the organ.
Due to our precise experimental control of the activation and deactivation of the CB neurogenic niche, we believe the CB is
an ideal model to study fundamental questions about adult neural stem cell physiology and the interaction with the niche. We
propose to study the cellular and molecular mechanisms by which these carotid body stem cells enter and exit the quiescent
state, which will help us understand the physiology of adult neurogenic niches. Likewise, understanding this neurogenic
process will improve the efficacy of using glomus cells for cell therapy against neurological disease, and might help us
understand some neural tumors.
Max ERC Funding
1 476 000 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
Project acronym CLR SENSING NECROSIS
Project Immune Functions of Myeloid Syk-coupled C-type Lectin Receptors Sensing Necrosis
Researcher (PI) David Sancho Madrid
Host Institution (HI) CENTRO NACIONAL DE INVESTIGACIONESCARDIOVASCULARES CARLOS III (F.S.P.)
Call Details Starting Grant (StG), LS6, ERC-2010-StG_20091118
Summary Necrosis triggers an inflammatory response driven by macrophages that normally contributes to tissue repair but, under certain conditions, can induce a state of chronic inflammation that forms the basis of many diseases. In addition, dendritic cell (DC)-mediated presentation of antigens from necrotic cells can trigger adaptive immunity in infection-free situations, such as autoimmunity or therapy-induced tumour rejection. Recently, we and others have identified the myeloid C-type lectin receptors (CLRs) CLEC9A (DNGR-1), in DC, and Mincle, in macrophages, as receptors for necrotic cells that can signal via the Syk kinase. Previous studies on similar Syk-coupled CLRs showed that Dectin-1 and Dectin-2 can induce innate and adaptive immune responses. We thus hypothesise that recognition of cell death by myeloid Syk-coupled CLRs is at the root of immune pathologies associated with accumulation of dead cells. The overall objective of this proposal is to investigate necrosis sensing by myeloid cells as a trigger of immunity and to study the underlying molecular mechanisms. Our first goal is to characterise signalling and gene induction via CLEC9A as a model necrosis receptor in DCs. Second, we will investigate the role of myeloid Syk-coupled necrosis-sensing CLRs in animal models of atherosclerosis, lupus and immunity to chemotherapy-treated tumours. Our preliminary data suggest that additional receptors can couple necrosis recognition to the Syk pathway in DC; thus, our third aim is to identify novel myeloid Syk-coupled receptors for necrotic cells. Characterisation of the outcomes of sensing necrosis by myeloid Syk-coupled receptors and their effect on the proposed pathologies promises to identify new mechanisms and targets for the treatment of these diseases.
Summary
Necrosis triggers an inflammatory response driven by macrophages that normally contributes to tissue repair but, under certain conditions, can induce a state of chronic inflammation that forms the basis of many diseases. In addition, dendritic cell (DC)-mediated presentation of antigens from necrotic cells can trigger adaptive immunity in infection-free situations, such as autoimmunity or therapy-induced tumour rejection. Recently, we and others have identified the myeloid C-type lectin receptors (CLRs) CLEC9A (DNGR-1), in DC, and Mincle, in macrophages, as receptors for necrotic cells that can signal via the Syk kinase. Previous studies on similar Syk-coupled CLRs showed that Dectin-1 and Dectin-2 can induce innate and adaptive immune responses. We thus hypothesise that recognition of cell death by myeloid Syk-coupled CLRs is at the root of immune pathologies associated with accumulation of dead cells. The overall objective of this proposal is to investigate necrosis sensing by myeloid cells as a trigger of immunity and to study the underlying molecular mechanisms. Our first goal is to characterise signalling and gene induction via CLEC9A as a model necrosis receptor in DCs. Second, we will investigate the role of myeloid Syk-coupled necrosis-sensing CLRs in animal models of atherosclerosis, lupus and immunity to chemotherapy-treated tumours. Our preliminary data suggest that additional receptors can couple necrosis recognition to the Syk pathway in DC; thus, our third aim is to identify novel myeloid Syk-coupled receptors for necrotic cells. Characterisation of the outcomes of sensing necrosis by myeloid Syk-coupled receptors and their effect on the proposed pathologies promises to identify new mechanisms and targets for the treatment of these diseases.
Max ERC Funding
1 297 671 €
Duration
Start date: 2010-12-01, End date: 2016-08-31
Project acronym EPINORC
Project Epigenetic Disruption of Non-Coding RNAs in Human Cancer
Researcher (PI) Manel Esteller Badosa
Host Institution (HI) FUNDACIO INSTITUT D'INVESTIGACIO BIOMEDICA DE BELLVITGE
Call Details Advanced Grant (AdG), LS4, ERC-2010-AdG_20100317
Summary In recent years, my laboratory, as well as others, have established the observation that epigenetic disruption, particularly in the DNA methylation and histone modification patterns, contributes to the initiation and progression of human tumors (Esteller, Nat Rev Genet 2007; Esteller, N Engl J Med 2008; Esteller, Nat Rev Biotech, In Press, 2010). Even more recently, it has been recognized that microRNAs, small non-coding RNAs that are thought to regulate gene expression by sequence-specific base pairing in mRNA targets, also play a key role in the biology of the cell, and that they can also have an impact in the development of many diseases, including cancer (le Sage and Agami, 2006; Blenkiron and Miska, 2007). However, there is little understanding about epigenetic modifications that might regulate the activity of microRNAs and other non-coding RNAs (ncRNAs), such as long non-coding RNAs (lncRNAs), Piwi-interacting RNAs (piRNAs), small-interfering RNAs (siRNAs), transcribed ultraconserved regions (T-UCRs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), long interspersed ncRNAs (lincRNAs), promoter-associated RNAs (PASRs and PALRs) and terminator-associated sRNAs (TASRs) (Calin et al., 2007; Mercer, et al., 2009; Ghildiyal & Zamore, 2009; Jacquier, 2009). Our ignorance in this respect is even more significant if we consider these questions in the domain of cancer. Making best use of our expertise in several of these fields, my group will tackle the study of the epigenetic modifications that regulate ncRNA expression and how the DNA methylation and histone modifications profiles of these loci might become distorted in human cancer. These findings could have profound consequences not only in the understading of tumor biology, but in the design of better molecular staging, diagnosis and treatments of human malignancies.
Summary
In recent years, my laboratory, as well as others, have established the observation that epigenetic disruption, particularly in the DNA methylation and histone modification patterns, contributes to the initiation and progression of human tumors (Esteller, Nat Rev Genet 2007; Esteller, N Engl J Med 2008; Esteller, Nat Rev Biotech, In Press, 2010). Even more recently, it has been recognized that microRNAs, small non-coding RNAs that are thought to regulate gene expression by sequence-specific base pairing in mRNA targets, also play a key role in the biology of the cell, and that they can also have an impact in the development of many diseases, including cancer (le Sage and Agami, 2006; Blenkiron and Miska, 2007). However, there is little understanding about epigenetic modifications that might regulate the activity of microRNAs and other non-coding RNAs (ncRNAs), such as long non-coding RNAs (lncRNAs), Piwi-interacting RNAs (piRNAs), small-interfering RNAs (siRNAs), transcribed ultraconserved regions (T-UCRs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), long interspersed ncRNAs (lincRNAs), promoter-associated RNAs (PASRs and PALRs) and terminator-associated sRNAs (TASRs) (Calin et al., 2007; Mercer, et al., 2009; Ghildiyal & Zamore, 2009; Jacquier, 2009). Our ignorance in this respect is even more significant if we consider these questions in the domain of cancer. Making best use of our expertise in several of these fields, my group will tackle the study of the epigenetic modifications that regulate ncRNA expression and how the DNA methylation and histone modifications profiles of these loci might become distorted in human cancer. These findings could have profound consequences not only in the understading of tumor biology, but in the design of better molecular staging, diagnosis and treatments of human malignancies.
Max ERC Funding
2 497 240 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym LEK
Project The adaptive nature of culture. A cross-cultural analysis of the returns of Local Environmental Knowledge in three indigenous societies
Researcher (PI) Victoria Reyes García
Host Institution (HI) UNIVERSITAT AUTONOMA DE BARCELONA
Call Details Starting Grant (StG), SH3, ERC-2010-StG_20091209
Summary Researchers debate the role of culture in shaping human adaptive strategy. Some researchers suggest that the behavioural adaptations that explain the success of our species are partially cultural, i.e., cumulative and transmitted by social learning.
Others find that cultural knowledge has often resulted in maladaptive practices, loss of technologies, and societies collapse.
Despite the importance of the debate, we lack empirical, comparative, research on the mechanisms through which culture might shape human adaptation. I will collect real world data to test a pathway through which cultural knowledge might
enhance human adaptive strategy: the individual returns to culturally evolved and environment-specific knowledge. I will direct two post-docs and four PhD students who will collect six sets of comparable panel data in three foraging societies:
the Tsimane (Amazon), the Baka (Congo Basin), and the Penan (Borneo). I will use a culturally-specific but cross-culturally comparative method to assess individual local knowledge related to 1) wild edibles; 2) medicine; 3) agriculture; and 4) weather forecast. I will analyze data using instrumental variables to get rigorous estimates of the returns to knowledge on
a) own and offsprings health and b) nutritional status, and c) farming and d) foraging productivity. Data would allow me to make generalizations on 1) the returns to local environmental knowledge and 2) the conditions under which locally developed
knowledge is adaptive or ceases to be so. The ground-breaking nature of this study lies in its explicit attempt to use empirical data and a cross-cultural framework to provide a first test of the adaptive nature of culturally transmitted information, and to do so by linking cultural knowledge to individual outcomes.
Summary
Researchers debate the role of culture in shaping human adaptive strategy. Some researchers suggest that the behavioural adaptations that explain the success of our species are partially cultural, i.e., cumulative and transmitted by social learning.
Others find that cultural knowledge has often resulted in maladaptive practices, loss of technologies, and societies collapse.
Despite the importance of the debate, we lack empirical, comparative, research on the mechanisms through which culture might shape human adaptation. I will collect real world data to test a pathway through which cultural knowledge might
enhance human adaptive strategy: the individual returns to culturally evolved and environment-specific knowledge. I will direct two post-docs and four PhD students who will collect six sets of comparable panel data in three foraging societies:
the Tsimane (Amazon), the Baka (Congo Basin), and the Penan (Borneo). I will use a culturally-specific but cross-culturally comparative method to assess individual local knowledge related to 1) wild edibles; 2) medicine; 3) agriculture; and 4) weather forecast. I will analyze data using instrumental variables to get rigorous estimates of the returns to knowledge on
a) own and offsprings health and b) nutritional status, and c) farming and d) foraging productivity. Data would allow me to make generalizations on 1) the returns to local environmental knowledge and 2) the conditions under which locally developed
knowledge is adaptive or ceases to be so. The ground-breaking nature of this study lies in its explicit attempt to use empirical data and a cross-cultural framework to provide a first test of the adaptive nature of culturally transmitted information, and to do so by linking cultural knowledge to individual outcomes.
Max ERC Funding
1 000 000 €
Duration
Start date: 2011-01-01, End date: 2015-12-31
Project acronym LONGCHROM
Project Chromosome Segregation and Aneuploidy
Researcher (PI) Manuel Ernesto Mendoza Palomares
Host Institution (HI) FUNDACIO CENTRE DE REGULACIO GENOMICA
Call Details Starting Grant (StG), LS3, ERC-2010-StG_20091118
Summary Accurate partitioning of the genetic material during cell division is critical for genetic stability. Defects in chromosome segregation produce aneuploidy, an unequal distribution of chromosomes between daughter cells, which is cause of developmental defects, and one of the cancer hallmarks. To ensure error-free transmission of chromosomes, feedback control systems verify that processes at each stage of the cycle have been completed before progression into the next stage. In particular, the spindle assembly checkpoint prevents initiation of anaphase until chromosomes attach properly to the spindle, whereas the NoCut checkpoint, which I identified, delays cytokinesis until chromosome segregation is complete. The discovery of NoCut, which is conserved from yeast to humans, reveals that eukaryotic cells monitor chromosome segregation during anaphase. The molecular mechanisms of this, and potentially other anaphase feedback controls remain obscure.
The goal of this proposal is to achieve a detailed understanding of the mechanisms coordinating chromosome segregation and cytokinesis. Key to this task will be the experimental manipulation of chromosome architecture in budding yeast, which allows the generation of cells with extra long chromosome arms. Using this strategy, we have already uncovered one novel feedback system, which monitors axial chromosome compaction during anaphase. We will investigate this and other anaphase controls through a multidisciplinary approach, which combines genetic techniques with state-of-the-art live cell microscopy, genomics and proteomics. We will characterize the feedback mechanism controlling chromosome compaction, and the molecular basis of chromosome segregation errors during anaphase. The relevance of these novel processes will be confirmed by analysis of cell division in animal cells and in a Drosophila tumour model. These approaches will advance our understanding of how eukaryotic cells prevent aneuploidy and tumorigenesis.
Summary
Accurate partitioning of the genetic material during cell division is critical for genetic stability. Defects in chromosome segregation produce aneuploidy, an unequal distribution of chromosomes between daughter cells, which is cause of developmental defects, and one of the cancer hallmarks. To ensure error-free transmission of chromosomes, feedback control systems verify that processes at each stage of the cycle have been completed before progression into the next stage. In particular, the spindle assembly checkpoint prevents initiation of anaphase until chromosomes attach properly to the spindle, whereas the NoCut checkpoint, which I identified, delays cytokinesis until chromosome segregation is complete. The discovery of NoCut, which is conserved from yeast to humans, reveals that eukaryotic cells monitor chromosome segregation during anaphase. The molecular mechanisms of this, and potentially other anaphase feedback controls remain obscure.
The goal of this proposal is to achieve a detailed understanding of the mechanisms coordinating chromosome segregation and cytokinesis. Key to this task will be the experimental manipulation of chromosome architecture in budding yeast, which allows the generation of cells with extra long chromosome arms. Using this strategy, we have already uncovered one novel feedback system, which monitors axial chromosome compaction during anaphase. We will investigate this and other anaphase controls through a multidisciplinary approach, which combines genetic techniques with state-of-the-art live cell microscopy, genomics and proteomics. We will characterize the feedback mechanism controlling chromosome compaction, and the molecular basis of chromosome segregation errors during anaphase. The relevance of these novel processes will be confirmed by analysis of cell division in animal cells and in a Drosophila tumour model. These approaches will advance our understanding of how eukaryotic cells prevent aneuploidy and tumorigenesis.
Max ERC Funding
1 058 610 €
Duration
Start date: 2011-06-01, End date: 2017-05-31
Project acronym MUPS
Project Mechanism of Unconventional Protein Secretion
Researcher (PI) Vivek Malhotra
Host Institution (HI) FUNDACIO CENTRE DE REGULACIO GENOMICA
Call Details Advanced Grant (AdG), LS3, ERC-2010-AdG_20100317
Summary Approximately 30% of the human genes encode proteins that enter the Endoplasmic Reticulum (ER) by a hydrophobic sequence called the signal sequence. Most of these proteins are transported to the Golgi apparatus for sorting and subsequent delivery to the endosomes, cell surface, and the extracellular space. There is good understanding of this process of ¿conventional¿ protein secretion. Surprisingly, there is another class of cytoplasmic proteins that are secreted even though they a lack signal sequence to enter the ER. How are such proteins secreted? The yeast protein a-factor achieves this goal by direct transport across the plasma membrane via an ABC transporter encoded by the STE6 gene. Little else of significance is known about this ¿unconventional¿ secretory pathway.
Our new findings reveal that secretion of signal sequence lacking acyl-coA binding protein or Acb1 in Saccharomyces cerevisae and Pichia pastoris requires autophagy related genes, fusion of membranes with early endosomes, formation of multivesicular body and the plasma membrane fusion protein (t-SNARE) called Sso1p. Our results indicate that secretion of Acb1 is mediated by a secretory autophagosomes. The secretion of Acb1 therefore does not follow the same pathway as the a-factor. But how is Acb1 packed into an autophagosome and why doesn¿t the secretory autophagosome fuse with the vacuole? In other words what is the difference between a secretory and a degradative autophagosome? Does an autophagosome-like vesicle also secrete cytokines, which lack a signal sequence to enter the ER? Our aim is to address these key questions. Many unconventionally secreted proteins regulate tissue organization, behavior (anxiety and addiction), angiogenesis, immune surveillance and diabetes. Understanding the mechanism of this poorly understood process is therefore of fundamental importance.
Summary
Approximately 30% of the human genes encode proteins that enter the Endoplasmic Reticulum (ER) by a hydrophobic sequence called the signal sequence. Most of these proteins are transported to the Golgi apparatus for sorting and subsequent delivery to the endosomes, cell surface, and the extracellular space. There is good understanding of this process of ¿conventional¿ protein secretion. Surprisingly, there is another class of cytoplasmic proteins that are secreted even though they a lack signal sequence to enter the ER. How are such proteins secreted? The yeast protein a-factor achieves this goal by direct transport across the plasma membrane via an ABC transporter encoded by the STE6 gene. Little else of significance is known about this ¿unconventional¿ secretory pathway.
Our new findings reveal that secretion of signal sequence lacking acyl-coA binding protein or Acb1 in Saccharomyces cerevisae and Pichia pastoris requires autophagy related genes, fusion of membranes with early endosomes, formation of multivesicular body and the plasma membrane fusion protein (t-SNARE) called Sso1p. Our results indicate that secretion of Acb1 is mediated by a secretory autophagosomes. The secretion of Acb1 therefore does not follow the same pathway as the a-factor. But how is Acb1 packed into an autophagosome and why doesn¿t the secretory autophagosome fuse with the vacuole? In other words what is the difference between a secretory and a degradative autophagosome? Does an autophagosome-like vesicle also secrete cytokines, which lack a signal sequence to enter the ER? Our aim is to address these key questions. Many unconventionally secreted proteins regulate tissue organization, behavior (anxiety and addiction), angiogenesis, immune surveillance and diabetes. Understanding the mechanism of this poorly understood process is therefore of fundamental importance.
Max ERC Funding
2 206 963 €
Duration
Start date: 2011-08-01, End date: 2016-07-31
Project acronym OBECAN
Project Role of obesity in the development of hepatocellular carcinoma
Researcher (PI) Guadalupe Sabio Buzo
Host Institution (HI) CENTRO NACIONAL DE INVESTIGACIONESCARDIOVASCULARES CARLOS III (F.S.P.)
Call Details Starting Grant (StG), LS4, ERC-2010-StG_20091118
Summary Obesity is associated with increased risk for epithelial tumors such as hepatocellular carcinoma (HCC). It is not known, however, whether obesity increases the risk for HCC simply because it promotes cirrhosis, a general risk factor for HCC, or through other mechanisms that operate independently of cirrhosis. Among these, obesity is associated with a chronic inflammatory state, with the release of cytokines such as IL-6 and TNFalpha, well-known HCC mediators. Obesity is normally linked to diabetes and in consequence, to hyperinsulinemia. This increase in circulating insulin levels is suggested to be a factor that contributes to cancer. Moreover, the increase in free fatty acids (FFA) in blood among obese patients promotes a compensatory response from liver that activates the transcription of genes required for beta-oxidation, leading to a reduction in non-physiological stores of lipids in the liver. This increase in beta-oxidation could result in oxidative stress, inflammation and the production of lipid peroxidation bioproducts, which are known mutagens. The precise mechanisms whereby FFA and cytosolic triglycerides exert their effects, resulting in the diabetic phenotype, remain poorly understood. Emerging evidence nonetheless links microRNA (miRNA) with lipid metabolism, suggesting that these small RNAs mediate this increase in beta-oxidation.
Our goal is to study how the components of the obesity state (inflammation, steatosis hyperinsulinemia and microRNA control of gene regulation) affect HCC development. We will use several mouse models in which one or more of these factors are reduced following induction of metabolic disease. We will also determine whether specific miRNAs that are down- or upregulated in the liver of mice on a high fat diet are implicated in HCC development.
Summary
Obesity is associated with increased risk for epithelial tumors such as hepatocellular carcinoma (HCC). It is not known, however, whether obesity increases the risk for HCC simply because it promotes cirrhosis, a general risk factor for HCC, or through other mechanisms that operate independently of cirrhosis. Among these, obesity is associated with a chronic inflammatory state, with the release of cytokines such as IL-6 and TNFalpha, well-known HCC mediators. Obesity is normally linked to diabetes and in consequence, to hyperinsulinemia. This increase in circulating insulin levels is suggested to be a factor that contributes to cancer. Moreover, the increase in free fatty acids (FFA) in blood among obese patients promotes a compensatory response from liver that activates the transcription of genes required for beta-oxidation, leading to a reduction in non-physiological stores of lipids in the liver. This increase in beta-oxidation could result in oxidative stress, inflammation and the production of lipid peroxidation bioproducts, which are known mutagens. The precise mechanisms whereby FFA and cytosolic triglycerides exert their effects, resulting in the diabetic phenotype, remain poorly understood. Emerging evidence nonetheless links microRNA (miRNA) with lipid metabolism, suggesting that these small RNAs mediate this increase in beta-oxidation.
Our goal is to study how the components of the obesity state (inflammation, steatosis hyperinsulinemia and microRNA control of gene regulation) affect HCC development. We will use several mouse models in which one or more of these factors are reduced following induction of metabolic disease. We will also determine whether specific miRNAs that are down- or upregulated in the liver of mice on a high fat diet are implicated in HCC development.
Max ERC Funding
1 498 043 €
Duration
Start date: 2010-12-01, End date: 2016-11-30
Project acronym PLANT CIRES BIOTECH
Project Functional characterization of plant cellular IRES in response to abiotic stress and their use as biotechnological tools
Researcher (PI) María Del Mar Castellano
Host Institution (HI) INSTITUTO NACIONAL DE INVESTIGACION Y TECNOLOGIA AGRARIA Y ALIMENTARIA OA MP
Call Details Starting Grant (StG), LS9, ERC-2010-StG_20091118
Summary To cope with abiotic stresses plants require an extensive molecular regulation of gene expression. In plants, translation is a key step in the control of gene expression under abiotic stress conditions. This translational regulation involves (1) a global inhibition of protein synthesis and (2) an efficient and selective translation of certain mRNAs, generally codifying proteins involved in the abiotic stress response. Although in plants the mechanisms involved in the onset of this dual regulation are currently unknown, some evidences point out that cap independent translation, via recognition of internal ribosome entry sites (IRES) within the mRNAs efficiently translated, could be the clue for the selective protein synthesis observed under such conditions.
In this proposal we aim to further characterize the cellular IRESs operating under abiotic stress conditions in plants and to exploit the identified cellular IRESs as biotechnological tools to allow the efficient and selective translation of mRNAs of interest under abiotic stress conditions. In plants, no IRES trans-acting factors (ITAFs) and only two cellular IRESs have been identified so far. Therefore, the systematic identification of new cellular IRESs, the identification for the first time of ITAFs and the study of how they can control IRES activity-specificity under abiotic stress conditions are important steps forward in the knowledge of how plants adapt to environmental stresses. In addition, the pioneering use of the identified cellular IRESs as a tool to tightly and specifically control the expression of proteins of interest under abiotic stress conditions will open up a new perspective for the study of abiotic stress in plants and for the generation of plants with increased tolerance to such conditions.
Summary
To cope with abiotic stresses plants require an extensive molecular regulation of gene expression. In plants, translation is a key step in the control of gene expression under abiotic stress conditions. This translational regulation involves (1) a global inhibition of protein synthesis and (2) an efficient and selective translation of certain mRNAs, generally codifying proteins involved in the abiotic stress response. Although in plants the mechanisms involved in the onset of this dual regulation are currently unknown, some evidences point out that cap independent translation, via recognition of internal ribosome entry sites (IRES) within the mRNAs efficiently translated, could be the clue for the selective protein synthesis observed under such conditions.
In this proposal we aim to further characterize the cellular IRESs operating under abiotic stress conditions in plants and to exploit the identified cellular IRESs as biotechnological tools to allow the efficient and selective translation of mRNAs of interest under abiotic stress conditions. In plants, no IRES trans-acting factors (ITAFs) and only two cellular IRESs have been identified so far. Therefore, the systematic identification of new cellular IRESs, the identification for the first time of ITAFs and the study of how they can control IRES activity-specificity under abiotic stress conditions are important steps forward in the knowledge of how plants adapt to environmental stresses. In addition, the pioneering use of the identified cellular IRESs as a tool to tightly and specifically control the expression of proteins of interest under abiotic stress conditions will open up a new perspective for the study of abiotic stress in plants and for the generation of plants with increased tolerance to such conditions.
Max ERC Funding
1 237 500 €
Duration
Start date: 2010-12-01, End date: 2017-05-31
Project acronym PRIMATESVS
Project Identification and characterization of primate structural variation and an assessment of intra-specific patterns of selection and copy-number variation
Researcher (PI) Tomas Marques Bonet
Host Institution (HI) UNIVERSIDAD POMPEU FABRA
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary Structural variation and copy-number variant regions (CNVs) (including segmental duplications) are usually underrepresented in genome analyses but are becoming a prominent feature in understanding the organization of genomes as well as many diseases. Large-scale comparative sequencing projects promised a golden era in the study of human evolution, however, many genome regions, especially these complicated regions, are clearly not solved.
Despite international efforts to characterize thousand of human genomes to understand the extent of structural variants in the human species, primates (our closest relatives) have somehow been forgotten. Yet, they are the ideal set of species to study the evolution of these features from both mechanistic and adaptive points of view. Most genome projects include only one individual as a reference but in order to understand the impact of structural variants in the evolution of every species we need to re-sequence multiple individuals of each species. We can only understand the origins of genomic variants and phenotypical differences among species if we can model variation within species and compare it to a proper perspective with the differences among species.
The object of this proposal is to discover the extent of genome structural polymorphism within the great ape species by generating next-generation sequencing datasets at high coverage from multiple individuals of diverse species and subspecies, characterizing structural variants and validating them experimentally. The results of these analyses will assess the rate of genome variation in primate evolution, characterize regional deletions and copy-number expansions as well as determine the patterns of selection acting upon them and whether the diversity of these segments is consistent with other forms of genetic variation among humans and great apes. In so doing, a fundamental insight will be provided into evolutionary variation of these regions among primates and into the mechanisms of disease-causing rearrangements with multiple repercussions in the understanding of evolution and human disease.
Summary
Structural variation and copy-number variant regions (CNVs) (including segmental duplications) are usually underrepresented in genome analyses but are becoming a prominent feature in understanding the organization of genomes as well as many diseases. Large-scale comparative sequencing projects promised a golden era in the study of human evolution, however, many genome regions, especially these complicated regions, are clearly not solved.
Despite international efforts to characterize thousand of human genomes to understand the extent of structural variants in the human species, primates (our closest relatives) have somehow been forgotten. Yet, they are the ideal set of species to study the evolution of these features from both mechanistic and adaptive points of view. Most genome projects include only one individual as a reference but in order to understand the impact of structural variants in the evolution of every species we need to re-sequence multiple individuals of each species. We can only understand the origins of genomic variants and phenotypical differences among species if we can model variation within species and compare it to a proper perspective with the differences among species.
The object of this proposal is to discover the extent of genome structural polymorphism within the great ape species by generating next-generation sequencing datasets at high coverage from multiple individuals of diverse species and subspecies, characterizing structural variants and validating them experimentally. The results of these analyses will assess the rate of genome variation in primate evolution, characterize regional deletions and copy-number expansions as well as determine the patterns of selection acting upon them and whether the diversity of these segments is consistent with other forms of genetic variation among humans and great apes. In so doing, a fundamental insight will be provided into evolutionary variation of these regions among primates and into the mechanisms of disease-causing rearrangements with multiple repercussions in the understanding of evolution and human disease.
Max ERC Funding
1 599 999 €
Duration
Start date: 2010-12-01, End date: 2014-11-30
