Project acronym APOLs
Project Role of Apolipoproteins L in immunity and disease
Researcher (PI) Etienne Pays
Host Institution (HI) UNIVERSITE LIBRE DE BRUXELLES
Call Details Advanced Grant (AdG), LS6, ERC-2014-ADG
Summary Work conducted in my laboratory on the trypanosome killing factor of human serum led to the identification
of the primate-specific Apolipoprotein L1 (APOL1) as a novel pore-forming protein with striking similarities
with proteins of the apoptotic BCL2 family. APOL1 belongs to a family of proteins induced under
inflammatory conditions in myeloid and endothelial cells. APOL1 is efficiently neutralized by the SRA
protein of Trypanosoma rhodesiense, accounting for the ability of this trypanosome subspecies to infect
humans and cause sleeping sickness. We found that natural APOL1 variants escaping SRA neutralization and
therefore conferring human resistance to T. rhodesiense are associated with chronic kidney disease.
Moreover, transgenic mice expressing these APOL1 variants exhibit an obese phenotype. Our unpublished
results also indicate that APOLs control the lifespan of dendritic cells and podocytes activated by viral
stimuli. Therefore, we propose that the pathology of APOL variants is due to their deregulated activity on the
control of the cellular lifespan in myeloid/endothelial cells activated by pathogen detection.
This project aims at characterizing (i) the molecular mechanism by which APOLs control the lifespan of
activated dendritic cells and podocytes, which has direct impact on innate immunity and inflammation, and
(ii) the mechanism by which APOL1 variants cause pathology. In addition, we plan to detail the
physiological function of APOLs by studying the phenotype of transgenic mice either expressing human
APOL1 (wild-type and variants) or devoid of APOL genes, which we have recently generated. Finally, we
propose to exploit the extraordinary potential of trypanosomes for antigenic variation in order to produce
SRA variants able to neutralize the pathogenic APOL1 variants. Preliminary experiments suggest that in
podocytes SRA antagonizes APOL1 induction by viral stimulus and subsequent cell death, opening new
perspectives to treat kidney disease.
Summary
Work conducted in my laboratory on the trypanosome killing factor of human serum led to the identification
of the primate-specific Apolipoprotein L1 (APOL1) as a novel pore-forming protein with striking similarities
with proteins of the apoptotic BCL2 family. APOL1 belongs to a family of proteins induced under
inflammatory conditions in myeloid and endothelial cells. APOL1 is efficiently neutralized by the SRA
protein of Trypanosoma rhodesiense, accounting for the ability of this trypanosome subspecies to infect
humans and cause sleeping sickness. We found that natural APOL1 variants escaping SRA neutralization and
therefore conferring human resistance to T. rhodesiense are associated with chronic kidney disease.
Moreover, transgenic mice expressing these APOL1 variants exhibit an obese phenotype. Our unpublished
results also indicate that APOLs control the lifespan of dendritic cells and podocytes activated by viral
stimuli. Therefore, we propose that the pathology of APOL variants is due to their deregulated activity on the
control of the cellular lifespan in myeloid/endothelial cells activated by pathogen detection.
This project aims at characterizing (i) the molecular mechanism by which APOLs control the lifespan of
activated dendritic cells and podocytes, which has direct impact on innate immunity and inflammation, and
(ii) the mechanism by which APOL1 variants cause pathology. In addition, we plan to detail the
physiological function of APOLs by studying the phenotype of transgenic mice either expressing human
APOL1 (wild-type and variants) or devoid of APOL genes, which we have recently generated. Finally, we
propose to exploit the extraordinary potential of trypanosomes for antigenic variation in order to produce
SRA variants able to neutralize the pathogenic APOL1 variants. Preliminary experiments suggest that in
podocytes SRA antagonizes APOL1 induction by viral stimulus and subsequent cell death, opening new
perspectives to treat kidney disease.
Max ERC Funding
2 250 000 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym BAS-SBBT
Project Bacterial Amyloid Secretion: Structural Biology and Biotechnology.
Researcher (PI) Han Karel Remaut
Host Institution (HI) VIB
Call Details Consolidator Grant (CoG), LS1, ERC-2014-CoG
Summary Curli are functional amyloid fibers that constitute the major protein component of the extracellular matrix in pellicle biofilms formed by Bacteroidetes and Proteobacteria. Unlike the protein misfolding and aggregation events seen in pathological amyloid diseases such as Alzheimer’s and Parkinson’s disease, curli are the product of a dedicated protein secretion machinery. Curli formation requires a specialised and mechanistically unique transporter in the bacterial outer membrane, as well as two soluble accessory proteins thought to facilitate the safe guidance of the curli subunits across the periplasm and to coordinate their self-assembly at cell surface.
In this interdisciplinary research program we will study the structural and molecular biology of E. coli curli biosynthesis and address the fundamental questions concerning the molecular processes that allow the spatially and temporally controlled transport and deposition of these pro-amyloidogenic polypeptides. We will structurally unravel the secretion machinery, trap and analyse critical secretion intermediates and through in vitro reconstitution, assemble a minimal, self-sufficient peptide transport and fiber assembly system.
The new insights gained will set the stage for targeted interventions in curli -mediated biofilm formation and this research project will develop a new framework to harness the unique properties found in curli structure and biosynthesis for biotechnological applications as in patterned functionalized nanowires and directed, selective peptide carriers.
Summary
Curli are functional amyloid fibers that constitute the major protein component of the extracellular matrix in pellicle biofilms formed by Bacteroidetes and Proteobacteria. Unlike the protein misfolding and aggregation events seen in pathological amyloid diseases such as Alzheimer’s and Parkinson’s disease, curli are the product of a dedicated protein secretion machinery. Curli formation requires a specialised and mechanistically unique transporter in the bacterial outer membrane, as well as two soluble accessory proteins thought to facilitate the safe guidance of the curli subunits across the periplasm and to coordinate their self-assembly at cell surface.
In this interdisciplinary research program we will study the structural and molecular biology of E. coli curli biosynthesis and address the fundamental questions concerning the molecular processes that allow the spatially and temporally controlled transport and deposition of these pro-amyloidogenic polypeptides. We will structurally unravel the secretion machinery, trap and analyse critical secretion intermediates and through in vitro reconstitution, assemble a minimal, self-sufficient peptide transport and fiber assembly system.
The new insights gained will set the stage for targeted interventions in curli -mediated biofilm formation and this research project will develop a new framework to harness the unique properties found in curli structure and biosynthesis for biotechnological applications as in patterned functionalized nanowires and directed, selective peptide carriers.
Max ERC Funding
1 989 489 €
Duration
Start date: 2015-06-01, End date: 2020-05-31
Project acronym BIFLOW
Project Bilingualism in Florentine and Tuscan Works (ca. 1260 - ca. 1416)
Researcher (PI) Antonio Montefusco
Host Institution (HI) UNIVERSITA CA' FOSCARI VENEZIA
Call Details Starting Grant (StG), SH5, ERC-2014-STG
Summary This project will undertake the first systematic investigation of the various literary documents that circulated simultaneously in more than one language in Tuscany, and especially Florence, between the mid-13th Century and the beginning of 15th Century.
During that period, Florence was both a prominent literary centre in the vernacular, and home to a renewal of classical Latin eloquence. While both fields are well studied, their interaction remains largely unexplored. This research, at the convergence of several disciplines (literature, philology, linguistics and medieval history), has a strong pioneering character. It aims at changing the perception of medieval Italian culture and interpretation of the break between medieval Culture and Humanism.
For this reason, the project will develop research in varying degrees of depth. First, it will provide the first catalogue of bilingual texts and manuscripts of medieval Tuscany. Organized as a database, this tool of analysis will stir innovative research in this field, some of which will be immediately promoted during the project.
Secondly, two case studies, considered as important and methodologically exemplary, will be researched in detail, through the publication of two important set of texts, of secular and religious nature : 1. The vernacular translation of the Latin Epistles of Dante Alighieri; 2. A collection of polemical, historiographical, devotional and prophetical documents produced by the Tuscan dissident Franciscans in last decades of the 14th Century.
Finally, the entire team, led by the PI, will be involved in the preparation of a synthesis volume on Tuscan culture in the fourteenth century viewed through bilingualism, entitled Cartography of bilingual culture in Fourteenth-Century Tuscany. From this general map of the Italian culture of the time, no literary genre nor field (be it religious or lay) shall be excluded.
Summary
This project will undertake the first systematic investigation of the various literary documents that circulated simultaneously in more than one language in Tuscany, and especially Florence, between the mid-13th Century and the beginning of 15th Century.
During that period, Florence was both a prominent literary centre in the vernacular, and home to a renewal of classical Latin eloquence. While both fields are well studied, their interaction remains largely unexplored. This research, at the convergence of several disciplines (literature, philology, linguistics and medieval history), has a strong pioneering character. It aims at changing the perception of medieval Italian culture and interpretation of the break between medieval Culture and Humanism.
For this reason, the project will develop research in varying degrees of depth. First, it will provide the first catalogue of bilingual texts and manuscripts of medieval Tuscany. Organized as a database, this tool of analysis will stir innovative research in this field, some of which will be immediately promoted during the project.
Secondly, two case studies, considered as important and methodologically exemplary, will be researched in detail, through the publication of two important set of texts, of secular and religious nature : 1. The vernacular translation of the Latin Epistles of Dante Alighieri; 2. A collection of polemical, historiographical, devotional and prophetical documents produced by the Tuscan dissident Franciscans in last decades of the 14th Century.
Finally, the entire team, led by the PI, will be involved in the preparation of a synthesis volume on Tuscan culture in the fourteenth century viewed through bilingualism, entitled Cartography of bilingual culture in Fourteenth-Century Tuscany. From this general map of the Italian culture of the time, no literary genre nor field (be it religious or lay) shall be excluded.
Max ERC Funding
1 480 625 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym CRADLE
Project Cancer treatment during pregnancy: from fetal safety to maternal efficacy
Researcher (PI) Frederic Amant
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary The evolution in drug regulation of the last 50 years has left pregnant women and their fetuses orphaned. This is particularly problematic for cancer during pregnancy, which raises a difficult and conflicting medical ethical decision process and which has recently become increasingly frequent. In 2012 we published the first prospective study indicating that antenatal exposure to cancer treatment can overall be considered safe. Building on this proof of concept, the current proposal wants to take a groundbreaking step towards developing a standard of care for cancer during pregnancy by addressing –in an integrated fashion- the challenges at the level of the fetus, the mother and the fetomaternal barrier. At the core of this proposal lies an international registry of pregnant women with cancer, along with a registry of their children, and biobanks of maternal, placental, cord blood and tumoral tissues. Research track ‘child’ aims to deliver robust evidence of fetal safety. Research track ‘mother’ aims to address the emerging concerns in the oncological management of the mother, and specifically, the possible distinct biology of pregnancy-associated breast cancer, the most frequent cancer type in pregnancy. The research approach includes large-scale clinical follow-up studies along with laboratory studies on patient biomaterials, including pharmacological investigations and RNA-sequencing studies. Complementary to these studies is research track ‘placenta’ in which cutting-edge models of human placental research are used to address the poorly understood physiological basis of the placental barrier function in this specific situation. This ambitious program will rely on a multidisciplinary team of experts. Not only may the scientific deliverables of this proposal constitute a major step forward to the well-being of both mother and fetus in a pregnancy complicated by cancer, the methodological approach may also provide critical impetus to further research in this field.
Summary
The evolution in drug regulation of the last 50 years has left pregnant women and their fetuses orphaned. This is particularly problematic for cancer during pregnancy, which raises a difficult and conflicting medical ethical decision process and which has recently become increasingly frequent. In 2012 we published the first prospective study indicating that antenatal exposure to cancer treatment can overall be considered safe. Building on this proof of concept, the current proposal wants to take a groundbreaking step towards developing a standard of care for cancer during pregnancy by addressing –in an integrated fashion- the challenges at the level of the fetus, the mother and the fetomaternal barrier. At the core of this proposal lies an international registry of pregnant women with cancer, along with a registry of their children, and biobanks of maternal, placental, cord blood and tumoral tissues. Research track ‘child’ aims to deliver robust evidence of fetal safety. Research track ‘mother’ aims to address the emerging concerns in the oncological management of the mother, and specifically, the possible distinct biology of pregnancy-associated breast cancer, the most frequent cancer type in pregnancy. The research approach includes large-scale clinical follow-up studies along with laboratory studies on patient biomaterials, including pharmacological investigations and RNA-sequencing studies. Complementary to these studies is research track ‘placenta’ in which cutting-edge models of human placental research are used to address the poorly understood physiological basis of the placental barrier function in this specific situation. This ambitious program will rely on a multidisciplinary team of experts. Not only may the scientific deliverables of this proposal constitute a major step forward to the well-being of both mother and fetus in a pregnancy complicated by cancer, the methodological approach may also provide critical impetus to further research in this field.
Max ERC Funding
2 000 000 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym DENOVOSTEM
Project DE NOVO GENERATION OF SOMATIC STEM CELLS: REGULATION AND MECHANISMS OF CELL PLASTICITY
Researcher (PI) Stefano Piccolo
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PADOVA
Call Details Advanced Grant (AdG), LS4, ERC-2014-ADG
Summary The possibility to artificially induce and expand in vitro tissue-specific stem cells (SCs) is an important goal for regenerative medicine, to understand organ physiology, for in vitro modeling of human diseases and many other applications. Here we found that this goal can be achieved in the culture dish by transiently inducing expression of YAP or TAZ - nuclear effectors of the Hippo and biomechanical pathways - into primary/terminally differentiated cells of distinct tissue origins. Moreover, YAP/TAZ are essential endogenous factors that preserve ex-vivo naturally arising SCs of distinct tissues.
In this grant, we aim to gain insights into YAP/TAZ molecular networks (upstream regulators and downstream targets) involved in somatic SC reprogramming and SC identity. Our studies will entail the identification of the genetic networks and epigenetic changes controlled by YAP/TAZ during cell de-differentiation and the re-acquisition of SC-traits in distinct cell types. We will also investigate upstream inputs establishing YAP/TAZ activity, with particular emphasis on biomechanical and cytoskeletal cues that represent overarching regulators of YAP/TAZ in tissues.
For many tumors, it appears that acquisition of an immature, stem-like state is a prerequisite for tumor progression and an early step in oncogene-mediated transformation. YAP/TAZ activation is widespread in human tumors. However, a connection between YAP/TAZ and oncogene-induced cell plasticity has never been investigated. We will also pursue some intriguing preliminary results and investigate how oncogenes and chromatin remodelers may link to cell mechanics, and the plasticity of the differentiated and SC states by controlling YAP/TAZ.
In sum, this research should advance our understanding of the cellular and molecular basis underpinning organ growth, tissue regeneration and tumor initiation.
Summary
The possibility to artificially induce and expand in vitro tissue-specific stem cells (SCs) is an important goal for regenerative medicine, to understand organ physiology, for in vitro modeling of human diseases and many other applications. Here we found that this goal can be achieved in the culture dish by transiently inducing expression of YAP or TAZ - nuclear effectors of the Hippo and biomechanical pathways - into primary/terminally differentiated cells of distinct tissue origins. Moreover, YAP/TAZ are essential endogenous factors that preserve ex-vivo naturally arising SCs of distinct tissues.
In this grant, we aim to gain insights into YAP/TAZ molecular networks (upstream regulators and downstream targets) involved in somatic SC reprogramming and SC identity. Our studies will entail the identification of the genetic networks and epigenetic changes controlled by YAP/TAZ during cell de-differentiation and the re-acquisition of SC-traits in distinct cell types. We will also investigate upstream inputs establishing YAP/TAZ activity, with particular emphasis on biomechanical and cytoskeletal cues that represent overarching regulators of YAP/TAZ in tissues.
For many tumors, it appears that acquisition of an immature, stem-like state is a prerequisite for tumor progression and an early step in oncogene-mediated transformation. YAP/TAZ activation is widespread in human tumors. However, a connection between YAP/TAZ and oncogene-induced cell plasticity has never been investigated. We will also pursue some intriguing preliminary results and investigate how oncogenes and chromatin remodelers may link to cell mechanics, and the plasticity of the differentiated and SC states by controlling YAP/TAZ.
In sum, this research should advance our understanding of the cellular and molecular basis underpinning organ growth, tissue regeneration and tumor initiation.
Max ERC Funding
2 498 934 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym ENVIROIMMUNE
Project Environmental modulators of the immune cell balance in health and disease
Researcher (PI) Markus Kleinewietfeld
Host Institution (HI) VIB
Call Details Starting Grant (StG), LS6, ERC-2014-STG
Summary The incidence of autoimmune diseases in developed societies is increasing at high rates, but the underlying cause for this phenomenon has not been elucidated yet. Since the genetic architect remains considerably stable, this increase is likely associated with changes in the environment. Autoimmunity is linked to an imbalance of pro-inflammatory Th17 cells and anti-inflammatory Foxp3+ regulatory T cells (Treg). However, little is known regarding environmental factors that influence the Th17/Treg balance. We recently discovered that a sodium-rich diet severely exacerbates experimental autoimmune encephalomyelitis (EAE) through an increased induction of pathogenic Th17 cells. Surprisingly, our preliminary data indicate that high-salt conditions also significantly impair Treg function, resembling a phenotype observed in several human autoimmune diseases. In addition, we have evidence that a high-salt diet affects the gut microbiota, implicating possible indirect effects on immune cells in vivo. Based on these findings we hypothesize that excess dietary salt represents an environmental risk factor for autoimmune diseases by modulating the Th17/Treg balance by several direct and indirect mechanisms. To address this hypothesis we will 1) examine the underlying mechanisms of high-salt induced Treg dysfunction and effects on the Treg/Th17 balance by molecular and functional analysis in vitro and compare it to known risk variants of human autoimmune diseases, and 2) define direct and indirect effects of excess dietary salt on the Th17/Treg balance and autoimmunity in vivo and explore potential novel pathways for targeted interventions. Thus, the proposed study will uncover the impact of a newly discovered environmental modulator of the immune cell balance and will ultimately pave the way for new approaches in therapy and prevention of autoimmune diseases.
Summary
The incidence of autoimmune diseases in developed societies is increasing at high rates, but the underlying cause for this phenomenon has not been elucidated yet. Since the genetic architect remains considerably stable, this increase is likely associated with changes in the environment. Autoimmunity is linked to an imbalance of pro-inflammatory Th17 cells and anti-inflammatory Foxp3+ regulatory T cells (Treg). However, little is known regarding environmental factors that influence the Th17/Treg balance. We recently discovered that a sodium-rich diet severely exacerbates experimental autoimmune encephalomyelitis (EAE) through an increased induction of pathogenic Th17 cells. Surprisingly, our preliminary data indicate that high-salt conditions also significantly impair Treg function, resembling a phenotype observed in several human autoimmune diseases. In addition, we have evidence that a high-salt diet affects the gut microbiota, implicating possible indirect effects on immune cells in vivo. Based on these findings we hypothesize that excess dietary salt represents an environmental risk factor for autoimmune diseases by modulating the Th17/Treg balance by several direct and indirect mechanisms. To address this hypothesis we will 1) examine the underlying mechanisms of high-salt induced Treg dysfunction and effects on the Treg/Th17 balance by molecular and functional analysis in vitro and compare it to known risk variants of human autoimmune diseases, and 2) define direct and indirect effects of excess dietary salt on the Th17/Treg balance and autoimmunity in vivo and explore potential novel pathways for targeted interventions. Thus, the proposed study will uncover the impact of a newly discovered environmental modulator of the immune cell balance and will ultimately pave the way for new approaches in therapy and prevention of autoimmune diseases.
Max ERC Funding
1 499 041 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
Project acronym EpiTALL
Project Dynamic interplay between DNA methylation, histone modifications and super enhancer activity in normal T cells and during malignant T cell transformation
Researcher (PI) Pieter Van vlierberghe
Host Institution (HI) UNIVERSITEIT GENT
Call Details Starting Grant (StG), LS4, ERC-2014-STG
Summary Dynamic interplay between histone modifications and DNA methylation defines the chromatin structure of the humane genome and serves as a conceptual framework to understand transcriptional regulation in normal development and human disease. The ultimate goal of this research proposal is to study the chromatin architecture during normal and malignant T cell differentiation in order to define how DNA methylation drives oncogenic gene expression as a novel concept in cancer research.
T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of pediatric and 25% of adult ALL cases and was originally identified as a highly aggressive tumor entity. T-ALL therapy has been intensified leading to gradual improvements in survival. However, 20% of pediatric and 50% of adult T-ALL cases still relapse and ultimately die because of refractory disease. Research efforts have unravelled the complex genetic basis of T-ALL but failed to identify new promising targets for precision therapy.
Recent studies have identified a subset of T-ALLs whose transcriptional programs resemble those of early T-cell progenitors (ETPs), myeloid precursors and hematopoietic stem cells. Importantly, these so-called ETP-ALLs are characterized by early treatment failure and an extremely poor prognosis. The unique ETP-ALL gene expression signature suggests that the epigenomic landscape in ETP-ALL is markedly different as compared to other genetic subtypes of human T-ALL.
My project aims to identify genome-wide patterns of DNA methylation and histone modifications in genetic subtypes of human T-ALL as a basis for elucidating how DNA methylation drives the expression of critical oncogenes in the context of poor prognostic ETP-ALL. Given that these ETP-ALL patients completely fail current chemotherapy treatment, tackling this completely novel aspect of ETP-ALL genetics will yield new targets for therapeutic intervention in this aggressive haematological malignancy.
Summary
Dynamic interplay between histone modifications and DNA methylation defines the chromatin structure of the humane genome and serves as a conceptual framework to understand transcriptional regulation in normal development and human disease. The ultimate goal of this research proposal is to study the chromatin architecture during normal and malignant T cell differentiation in order to define how DNA methylation drives oncogenic gene expression as a novel concept in cancer research.
T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of pediatric and 25% of adult ALL cases and was originally identified as a highly aggressive tumor entity. T-ALL therapy has been intensified leading to gradual improvements in survival. However, 20% of pediatric and 50% of adult T-ALL cases still relapse and ultimately die because of refractory disease. Research efforts have unravelled the complex genetic basis of T-ALL but failed to identify new promising targets for precision therapy.
Recent studies have identified a subset of T-ALLs whose transcriptional programs resemble those of early T-cell progenitors (ETPs), myeloid precursors and hematopoietic stem cells. Importantly, these so-called ETP-ALLs are characterized by early treatment failure and an extremely poor prognosis. The unique ETP-ALL gene expression signature suggests that the epigenomic landscape in ETP-ALL is markedly different as compared to other genetic subtypes of human T-ALL.
My project aims to identify genome-wide patterns of DNA methylation and histone modifications in genetic subtypes of human T-ALL as a basis for elucidating how DNA methylation drives the expression of critical oncogenes in the context of poor prognostic ETP-ALL. Given that these ETP-ALL patients completely fail current chemotherapy treatment, tackling this completely novel aspect of ETP-ALL genetics will yield new targets for therapeutic intervention in this aggressive haematological malignancy.
Max ERC Funding
958 750 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym EU-rhythmy
Project Molecular strategies to treat inherited arrhythmias
Researcher (PI) Silvia Giuliana Priori
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PAVIA
Call Details Advanced Grant (AdG), LS7, ERC-2014-ADG
Summary Sudden cardiac death (SCD) is a leading cause of death in western countries: coronary artery disease is the major cause of SCD in older subjects while inherited arrhythmogenic diseases are the leading cause of SCD in younger individuals. After 25 years dedicated to research of the molecular bases of heritable arrhythmias, the PI of this proposal now intends to pioneer gene therapy for prevention of SCD: a virtually unexplored field. The development of molecular therapies for rhythm disturbances is a high risk effort however, if successful, it will be highly rewarding. The PI has envisioned an ambitious and comprehensive project to target two severe inherited arrhythmogenic diseases: dominant catecholaminergic polymorphic ventricular tachycardia (CPVT) and Long QT syndrome type 8 (LQT8). The availability of a clinically relevant model is critical to ensure clinical translation of results: the team will exploit an existing CPVT model and will engineer a knock-in pig to model LQT8. The PI and her team will investigate innovative strategies of gene-delivery, gene-silencing and gene-editing to the heart comparing efficacy of different constructs and promoters. The team will also carefully engineer novel gene-therapy approaches to avoid the development of regional inhomogeneity in protein expression that may facilitate proarrhythmic events. Such a comprehensive approach will provide a most valuable core of knowledge on the comparative efficacy of a broad range of molecular strategies on the electrical milieu of the heart. It is expected that these results will not only benefit CPVT and LQT8 but rather they will foster development of gene therapy for other inherited and acquired arrhythmias.
Summary
Sudden cardiac death (SCD) is a leading cause of death in western countries: coronary artery disease is the major cause of SCD in older subjects while inherited arrhythmogenic diseases are the leading cause of SCD in younger individuals. After 25 years dedicated to research of the molecular bases of heritable arrhythmias, the PI of this proposal now intends to pioneer gene therapy for prevention of SCD: a virtually unexplored field. The development of molecular therapies for rhythm disturbances is a high risk effort however, if successful, it will be highly rewarding. The PI has envisioned an ambitious and comprehensive project to target two severe inherited arrhythmogenic diseases: dominant catecholaminergic polymorphic ventricular tachycardia (CPVT) and Long QT syndrome type 8 (LQT8). The availability of a clinically relevant model is critical to ensure clinical translation of results: the team will exploit an existing CPVT model and will engineer a knock-in pig to model LQT8. The PI and her team will investigate innovative strategies of gene-delivery, gene-silencing and gene-editing to the heart comparing efficacy of different constructs and promoters. The team will also carefully engineer novel gene-therapy approaches to avoid the development of regional inhomogeneity in protein expression that may facilitate proarrhythmic events. Such a comprehensive approach will provide a most valuable core of knowledge on the comparative efficacy of a broad range of molecular strategies on the electrical milieu of the heart. It is expected that these results will not only benefit CPVT and LQT8 but rather they will foster development of gene therapy for other inherited and acquired arrhythmias.
Max ERC Funding
2 314 029 €
Duration
Start date: 2015-11-01, End date: 2020-10-31
Project acronym HUMO
Project What is everybody doing? Social prediction, categorization, and monitoring in the Prefrontal Cortex of the Macaque adopting a new human-monkey (H-M) interactive paradigm.
Researcher (PI) Aldo Genovesio
Host Institution (HI) UNIVERSITA DEGLI STUDI DI ROMA LA SAPIENZA
Call Details Consolidator Grant (CoG), LS5, ERC-2014-CoG
Summary Primates live in a complex social environment, in which they need to maintain track of their past social interactions and learn to formulate prediction on what specific groupmates are likely to do based on their past experiences. I have previously contributed to show that the PF (prefrontal cortex) has a main function in the generation of goals based on the current contexts and events, but its role in social cognition is still little explored. In this context, the frontal Pole cortex (FPC) has been associated to “mentalizing” functions and there is a link between the autism spectrum disorder and its abnormalities. However until recently, no one has been able to record neural activity from FPC, but us. I propose to investigate the role of the monitoring function of FPC in association to the dorsolateral (PFD) and orbitofrontal (OFC) cortex, recording from the entire network up to 256 neurons simultaneously. We have developed the first human-monkeys (H-M) paradigm to test several hypotheses. The task is a non-match-to goal (NMTG) task in which the monkeys are trained to switch from their choice on the previous trial to a different one. In a subset of trials the monkey observe a human partner (either cooperative or uncooperative) performing the task. When the human partner conclude his turn, the monkeys have to switch to a new goal discarding the human’s previous goal. I will explore the role of PFD in social decisions in predicting other agents decisions and distinguishing and categorizing cooperative and uncooperative agents, and the role of OFC in monitoring others’ choices. I expect that PFD will maintain, as it does with past and future goals, separate records for the past choices of different agents while PFO might contribute to solve credit assignment problems also in relationship to other’s behaviors.
Summary
Primates live in a complex social environment, in which they need to maintain track of their past social interactions and learn to formulate prediction on what specific groupmates are likely to do based on their past experiences. I have previously contributed to show that the PF (prefrontal cortex) has a main function in the generation of goals based on the current contexts and events, but its role in social cognition is still little explored. In this context, the frontal Pole cortex (FPC) has been associated to “mentalizing” functions and there is a link between the autism spectrum disorder and its abnormalities. However until recently, no one has been able to record neural activity from FPC, but us. I propose to investigate the role of the monitoring function of FPC in association to the dorsolateral (PFD) and orbitofrontal (OFC) cortex, recording from the entire network up to 256 neurons simultaneously. We have developed the first human-monkeys (H-M) paradigm to test several hypotheses. The task is a non-match-to goal (NMTG) task in which the monkeys are trained to switch from their choice on the previous trial to a different one. In a subset of trials the monkey observe a human partner (either cooperative or uncooperative) performing the task. When the human partner conclude his turn, the monkeys have to switch to a new goal discarding the human’s previous goal. I will explore the role of PFD in social decisions in predicting other agents decisions and distinguishing and categorizing cooperative and uncooperative agents, and the role of OFC in monitoring others’ choices. I expect that PFD will maintain, as it does with past and future goals, separate records for the past choices of different agents while PFO might contribute to solve credit assignment problems also in relationship to other’s behaviors.
Max ERC Funding
1 028 750 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym INDIMACRO
Project Individual decisions and macroeconomic robustness
Researcher (PI) Massimo Marinacci
Host Institution (HI) UNIVERSITA COMMERCIALE LUIGI BOCCONI
Call Details Advanced Grant (AdG), SH1, ERC-2014-ADG
Summary Model uncertainty is a key issue and an active research area in Macro-Finance. Its study, pioneered by Hansen and Sargent, substantially improves the treatment of uncertainty in Macro-Finance models and the robustness of their conclusions. The interest of central banks on problems related to model uncertainty is a clear signal of the relevance of this novel concept and the related theoretical framework. Model uncertainty in Macro-Finance and ambiguity in Decision Theory share a common insight that inspires empirical and theoretical developments: the agents’ ignorance about the “true” probabilistic model that governs the uncertain environments they face. With few exceptions, decision theorists have studied ambiguity mostly in static contexts that are insufficient for the analysis of the steady state and dynamic decision problems that characterize Macro-Finance. Hence, this field keeps relying on decision models that cannot cope with model uncertainty.
Our research agenda aims to create a unified Macro-Finance and Decision Theory framework for the study of model uncertainty, which broadens the scope of Decision Theory and provides novel foundations for a common framework. We will build new steady state and dynamic decision models that are powerful enough for a general analysis of model uncertainty in Macro-Finance. We will also develop a self-confirming equilibrium analysis, which by leaving room for agents to have “wrong” views about models, can much more naturally confront agents with model uncertainty than the rational expectations approach. Our project will foster cross-fertilization and lead to a deeper understanding of the empirical and theoretical effects of uncertainty in Macro-Finance phenomena. Because model uncertainty is pervasive (e.g., which climate model to use? which is the correct production function for human capital?), we expect that our theoretical findings will push the research frontier and the analysis of the role of uncertainty in other fields.
Summary
Model uncertainty is a key issue and an active research area in Macro-Finance. Its study, pioneered by Hansen and Sargent, substantially improves the treatment of uncertainty in Macro-Finance models and the robustness of their conclusions. The interest of central banks on problems related to model uncertainty is a clear signal of the relevance of this novel concept and the related theoretical framework. Model uncertainty in Macro-Finance and ambiguity in Decision Theory share a common insight that inspires empirical and theoretical developments: the agents’ ignorance about the “true” probabilistic model that governs the uncertain environments they face. With few exceptions, decision theorists have studied ambiguity mostly in static contexts that are insufficient for the analysis of the steady state and dynamic decision problems that characterize Macro-Finance. Hence, this field keeps relying on decision models that cannot cope with model uncertainty.
Our research agenda aims to create a unified Macro-Finance and Decision Theory framework for the study of model uncertainty, which broadens the scope of Decision Theory and provides novel foundations for a common framework. We will build new steady state and dynamic decision models that are powerful enough for a general analysis of model uncertainty in Macro-Finance. We will also develop a self-confirming equilibrium analysis, which by leaving room for agents to have “wrong” views about models, can much more naturally confront agents with model uncertainty than the rational expectations approach. Our project will foster cross-fertilization and lead to a deeper understanding of the empirical and theoretical effects of uncertainty in Macro-Finance phenomena. Because model uncertainty is pervasive (e.g., which climate model to use? which is the correct production function for human capital?), we expect that our theoretical findings will push the research frontier and the analysis of the role of uncertainty in other fields.
Max ERC Funding
1 394 716 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
