Project acronym EURO-NEUROSTRESS
Project Dissecting the Central Stress Response: Bridging the Genotype-Phenotype Gap
Researcher (PI) Alon Chen
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary The biological response to stress is concerned with the maintenance of homeostasis in the presence of real or perceived challenges. This process requires numerous adaptive responses involving changes in the central nervous and neuroendocrine systems. When a situation is perceived as stressful, the brain activates many neuronal circuits linking centers involved in sensory, motor, autonomic, neuroendocrine, cognitive, and emotional functions in order to adapt to the demand. However, the details of the pathways by which the brain translates stressful stimuli into the final, integrated biological response are presently incompletely understood. Nevertheless, it is clear that dysregulation of these physiological responses to stress can have severe psychological and physiological consequences, and there is much evidence to suggest that inappropriate regulation, disproportional intensity, or chronic and/or irreversible activation of the stress response is linked to the etiology and pathophysiology of anxiety disorders and depression.
Understanding the neurobiology of stress by focusing on the brain circuits and genes, which are associated with, or altered by, the stress response will provide important insights into the brain mechanisms by which stress affects psychological and physiological disorders. This is an integrated multidisciplinary project from gene to behavior using state-of-the-art moue genetics and animal models. We will employ integrated molecular, biochemical, physiological and behavioral methods, focusing on the generation of mice genetic models as an in vivo tool, in order to study the central pathways and molecular mechanisms mediating the stress response. Defining the contributions of known and novel gene products to the maintenance of stress-linked homeostasis may improve our ability to design therapeutic interventions for, and thus manage, stress-related disorders.
Summary
The biological response to stress is concerned with the maintenance of homeostasis in the presence of real or perceived challenges. This process requires numerous adaptive responses involving changes in the central nervous and neuroendocrine systems. When a situation is perceived as stressful, the brain activates many neuronal circuits linking centers involved in sensory, motor, autonomic, neuroendocrine, cognitive, and emotional functions in order to adapt to the demand. However, the details of the pathways by which the brain translates stressful stimuli into the final, integrated biological response are presently incompletely understood. Nevertheless, it is clear that dysregulation of these physiological responses to stress can have severe psychological and physiological consequences, and there is much evidence to suggest that inappropriate regulation, disproportional intensity, or chronic and/or irreversible activation of the stress response is linked to the etiology and pathophysiology of anxiety disorders and depression.
Understanding the neurobiology of stress by focusing on the brain circuits and genes, which are associated with, or altered by, the stress response will provide important insights into the brain mechanisms by which stress affects psychological and physiological disorders. This is an integrated multidisciplinary project from gene to behavior using state-of-the-art moue genetics and animal models. We will employ integrated molecular, biochemical, physiological and behavioral methods, focusing on the generation of mice genetic models as an in vivo tool, in order to study the central pathways and molecular mechanisms mediating the stress response. Defining the contributions of known and novel gene products to the maintenance of stress-linked homeostasis may improve our ability to design therapeutic interventions for, and thus manage, stress-related disorders.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym GENEXP
Project Gene Expression Explored in Space and Time Using Single Gene and Single Molecule Analysis
Researcher (PI) Yaron Shav-Tal
Host Institution (HI) BAR ILAN UNIVERSITY
Call Details Starting Grant (StG), LS1, ERC-2010-StG_20091118
Summary "Live-cell imaging combined with kinetic analyses has provided new biological insights on the gene expression pathway. However, such studies in mammalian cells typically require use of exogenous over-expressed gene constructs, which often form large tandem gene arrays and usually lack the complete endogenous regulatory sequences. It is therefore imperative to design methodology for analyzing gene expression kinetics of single alleles of endogenous genes. While certain steps have been taken in this direction, there are many experimental obstacles standing in the way of a robust genome-wide system for the in vivo examination of endogenous gene expression within the natural nuclear environment. GENEXP sets out to provide such a system.
It will start with methodology for robust tagging of a multitude of endogenous genes and their transcribed mRNAs in human cells using the ""CD tagging"" approach. Thereby, in vivo mRNA synthesis at the nuclear site of RNA birth will be explored in a unique manner. A high-resolution study of gene expression, in particular mRNA transcription and mRNA export, under endogenous cellular context and using a genome-wide live-cell approach will be performed. GENEXP will specifically focus on the:
i) Transcriptional kinetics of endogenous genes in single cells and cell populations;
ii) Kinetics of mRNA export on the single molecule level;
iii) Examination of the protein composition of endogenous mRNPs;
iv) High throughput scan for drugs that affect gene expression and mRNA export.
Altogether, GENEXP will provide breakthrough capability in kinetically quantifying the gene expression pathway of a large variety of endogenous genes, and the ability to examine the generated molecules on the single-molecule level. This will be done within their normal genomic and biological environment, at the single-allele level."
Summary
"Live-cell imaging combined with kinetic analyses has provided new biological insights on the gene expression pathway. However, such studies in mammalian cells typically require use of exogenous over-expressed gene constructs, which often form large tandem gene arrays and usually lack the complete endogenous regulatory sequences. It is therefore imperative to design methodology for analyzing gene expression kinetics of single alleles of endogenous genes. While certain steps have been taken in this direction, there are many experimental obstacles standing in the way of a robust genome-wide system for the in vivo examination of endogenous gene expression within the natural nuclear environment. GENEXP sets out to provide such a system.
It will start with methodology for robust tagging of a multitude of endogenous genes and their transcribed mRNAs in human cells using the ""CD tagging"" approach. Thereby, in vivo mRNA synthesis at the nuclear site of RNA birth will be explored in a unique manner. A high-resolution study of gene expression, in particular mRNA transcription and mRNA export, under endogenous cellular context and using a genome-wide live-cell approach will be performed. GENEXP will specifically focus on the:
i) Transcriptional kinetics of endogenous genes in single cells and cell populations;
ii) Kinetics of mRNA export on the single molecule level;
iii) Examination of the protein composition of endogenous mRNPs;
iv) High throughput scan for drugs that affect gene expression and mRNA export.
Altogether, GENEXP will provide breakthrough capability in kinetically quantifying the gene expression pathway of a large variety of endogenous genes, and the ability to examine the generated molecules on the single-molecule level. This will be done within their normal genomic and biological environment, at the single-allele level."
Max ERC Funding
1 498 510 €
Duration
Start date: 2010-12-01, End date: 2015-11-30
Project acronym METSTEM
Project DNA methylation in stem cells
Researcher (PI) Howard Cedar
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), LS1, ERC-2010-AdG_20100317
Summary Embryonic and adult stem cells constitute an important component of biology by providing a pool of pluri- and multi-potent cells that supply a variety of different cell lineages. Little is known about the mechanisms involved in establishing and maintaining cell ¿stemness,¿ but it is most likely controlled by epigenetic signals such as DNA methylation. This proposal aims to understand these mechanisms and decipher the molecular logic used to program this plasticity.
We have developed a new strategy for studying the ¿DNA methylation potential¿ of any cell type throughout normal development. This utilizes a unique set of transgenic vectors programmed to detect both de novo methylation as well as the ability to protect CpG islands, and will, for the first time, allow one to evaluate the role of demethylation in normal stem cells and during reprogramming. This will be done using a new technique called ¿reverse epigenetics¿.
Preliminary studies indicate that embryonic stem cells differentiated in vitro undergo extensive aberrant methylation that does not reflect the normal pattern of methylation found in vivo. This artifact may be responsible for our inability to attain efficient differentiation in culture and may generate cells that are unhealthy and prone to cancer. We will characterize the causes of this phenomenon and decipher its underlying mechanism. This research should lead to the development of improved methods for tissue generation in vitro.
One of the most basic properties of adult stem cells is their ability to undergo asymmetric cell division that is often associated with unequal segregation of DNA. This mechanism is one of the most elemental, yet mysterious, aspects of stem cell biology. We have developed a completely new molecular model for this process that is based on the idea that non-symmetric DNA methylation serves as a strand-specific marker, and it is very likely that this will enable us to finally decipher this basic aspect of stem cells.
Summary
Embryonic and adult stem cells constitute an important component of biology by providing a pool of pluri- and multi-potent cells that supply a variety of different cell lineages. Little is known about the mechanisms involved in establishing and maintaining cell ¿stemness,¿ but it is most likely controlled by epigenetic signals such as DNA methylation. This proposal aims to understand these mechanisms and decipher the molecular logic used to program this plasticity.
We have developed a new strategy for studying the ¿DNA methylation potential¿ of any cell type throughout normal development. This utilizes a unique set of transgenic vectors programmed to detect both de novo methylation as well as the ability to protect CpG islands, and will, for the first time, allow one to evaluate the role of demethylation in normal stem cells and during reprogramming. This will be done using a new technique called ¿reverse epigenetics¿.
Preliminary studies indicate that embryonic stem cells differentiated in vitro undergo extensive aberrant methylation that does not reflect the normal pattern of methylation found in vivo. This artifact may be responsible for our inability to attain efficient differentiation in culture and may generate cells that are unhealthy and prone to cancer. We will characterize the causes of this phenomenon and decipher its underlying mechanism. This research should lead to the development of improved methods for tissue generation in vitro.
One of the most basic properties of adult stem cells is their ability to undergo asymmetric cell division that is often associated with unequal segregation of DNA. This mechanism is one of the most elemental, yet mysterious, aspects of stem cell biology. We have developed a completely new molecular model for this process that is based on the idea that non-symmetric DNA methylation serves as a strand-specific marker, and it is very likely that this will enable us to finally decipher this basic aspect of stem cells.
Max ERC Funding
1 941 930 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym MIRNACLOCKNETWORKS
Project Towards a systemic view of the circadian clock: Integration of miRNAs into the molecular, cellular and neural circadian networks
Researcher (PI) Sebastian Kadener
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary Circadian (24hs) rhythms in locomotor activity are one of the best-characterized behaviors at the molecular, cellular and neural levels. Despite that, our understanding of how these rhythms are generated is still limited. A major shortcoming of the current approaches in the field is that they depict the circadian clock as a mere addition of steps (and/or combination of parts). By doing so, the circadian oscillator is portrayed as a static rather than a dynamic system. We have recently shown for the first time that miRNA-mediated regulation plays a role in circadian timekeeping in Drosophila. In the present project we will exploit complementary and cutting-edge approaches that will provide an integrative and comprehensive view of the circadian timekeeping system. As we believe that miRNAs are key mediators of this integration, we will dissect their role in the circadian clock at the molecular, cellular and neural levels in Drosophila. At the molecular level, we will determine the mechanisms, and proteins that mediate the circadian regulation of miRNAs function. Moreover, by the use of high-throughput methodology we will assess and characterize the impact of translational regulation on both the circadian transcriptome and proteome. At the cellular level, we plan to determine how this type of regulation integrates with other circadian pathways and which specific pathways and proteins mediate this process. As a final goal of the proposed project we plan to generate a complete genetic interaction map of the known circadian regulators, which will integrate the different molecular and cellular events involved in timekeeping. This will be a key step towards the understanding of the circadian clock as a dynamic adjustable process. Last, but not least, we will study the role of miRNAs in the circadian neural network. For doing so we will set up an ex vivo approach (fly brain's culture) that will assess circadian parameters through fluorescent continuous live imaging.
Summary
Circadian (24hs) rhythms in locomotor activity are one of the best-characterized behaviors at the molecular, cellular and neural levels. Despite that, our understanding of how these rhythms are generated is still limited. A major shortcoming of the current approaches in the field is that they depict the circadian clock as a mere addition of steps (and/or combination of parts). By doing so, the circadian oscillator is portrayed as a static rather than a dynamic system. We have recently shown for the first time that miRNA-mediated regulation plays a role in circadian timekeeping in Drosophila. In the present project we will exploit complementary and cutting-edge approaches that will provide an integrative and comprehensive view of the circadian timekeeping system. As we believe that miRNAs are key mediators of this integration, we will dissect their role in the circadian clock at the molecular, cellular and neural levels in Drosophila. At the molecular level, we will determine the mechanisms, and proteins that mediate the circadian regulation of miRNAs function. Moreover, by the use of high-throughput methodology we will assess and characterize the impact of translational regulation on both the circadian transcriptome and proteome. At the cellular level, we plan to determine how this type of regulation integrates with other circadian pathways and which specific pathways and proteins mediate this process. As a final goal of the proposed project we plan to generate a complete genetic interaction map of the known circadian regulators, which will integrate the different molecular and cellular events involved in timekeeping. This will be a key step towards the understanding of the circadian clock as a dynamic adjustable process. Last, but not least, we will study the role of miRNAs in the circadian neural network. For doing so we will set up an ex vivo approach (fly brain's culture) that will assess circadian parameters through fluorescent continuous live imaging.
Max ERC Funding
1 478 606 €
Duration
Start date: 2011-02-01, End date: 2016-01-31
Project acronym RRHEDSPS
Project Reconsidering Representation: How Electoral Districts Shape Party Systems
Researcher (PI) Orit Kedar
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), SH2, ERC-2010-StG_20091209
Summary An electoral system is an essential component of representative democracy. It translates preferences
of citizens to a legislative body and inevitably distorts preferences, voicing some more loudly than others.
Theorizing and empirically analyzing how the electoral system tilts the playing ground is the aim of this
study.
The number of seats allotted to an electoral district—the district magnitude (DM)—is perhaps the
most important component defining an electoral system. It is long established that DM affects key features
of the political landscape in a country, such as representation, the number of parties, the type of government
(single- or multi-party coalition), parties’ strategy, voters’ consideration, and even redistribution policy.
Most democracies, however, have districts of many different magnitudes, and the range often reaches thirty
seats gap between the smallest and largest districts in a country. Districts in Portugal, for instance, vary
between two and forty-eight seats, and in Switzerland between one and thirty-five. The voluminous
literature on electoral districts uniformly sidesteps this heterogeneity, focusing instead on a single middle
district per country.
The proposed study is the first large-scale study that theorizes about and empirically analyzes the
effects of within-country district structure. I address questions such as: how does district heterogeneity
shape representation at the national level? How does it affect the party system? And how does it affect party
coordination?
In the first part of the study I will theorize about various aspects of district heterogeneity in a country
(e.g., skewness, effective number of magnitudes). I will gain deep understanding for district distributions
and develop politically-relevant measures of heterogeneity. Drawing on insights from the theoretical part,
the second part will empirically examine how district heterogeneity affects the political landscape, and in
particular representation, party system, and party coordination. This part relies on extensive district- and
national-level data collection and data analysis in OECD countries as well as in-depth case analysis.
Analyzing the effect of district heterogeneity on representation, party systems, and party
coordination will open new avenues of research about design of electoral systems.
Summary
An electoral system is an essential component of representative democracy. It translates preferences
of citizens to a legislative body and inevitably distorts preferences, voicing some more loudly than others.
Theorizing and empirically analyzing how the electoral system tilts the playing ground is the aim of this
study.
The number of seats allotted to an electoral district—the district magnitude (DM)—is perhaps the
most important component defining an electoral system. It is long established that DM affects key features
of the political landscape in a country, such as representation, the number of parties, the type of government
(single- or multi-party coalition), parties’ strategy, voters’ consideration, and even redistribution policy.
Most democracies, however, have districts of many different magnitudes, and the range often reaches thirty
seats gap between the smallest and largest districts in a country. Districts in Portugal, for instance, vary
between two and forty-eight seats, and in Switzerland between one and thirty-five. The voluminous
literature on electoral districts uniformly sidesteps this heterogeneity, focusing instead on a single middle
district per country.
The proposed study is the first large-scale study that theorizes about and empirically analyzes the
effects of within-country district structure. I address questions such as: how does district heterogeneity
shape representation at the national level? How does it affect the party system? And how does it affect party
coordination?
In the first part of the study I will theorize about various aspects of district heterogeneity in a country
(e.g., skewness, effective number of magnitudes). I will gain deep understanding for district distributions
and develop politically-relevant measures of heterogeneity. Drawing on insights from the theoretical part,
the second part will empirically examine how district heterogeneity affects the political landscape, and in
particular representation, party system, and party coordination. This part relies on extensive district- and
national-level data collection and data analysis in OECD countries as well as in-depth case analysis.
Analyzing the effect of district heterogeneity on representation, party systems, and party
coordination will open new avenues of research about design of electoral systems.
Max ERC Funding
1 038 686 €
Duration
Start date: 2010-11-01, End date: 2016-10-31
Project acronym SIAMCP
Project Follow the PAIN: Novel Somatotopically-Based Integrative Approach to Study Mechanisms of Detection, Transmission and Perpetuation of Nociceptive, Inflammatory and Neuropathic Pain
Researcher (PI) Alexander Binshtok
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary The worst of evils - pain is one of the main reasons for seeking medical help. Chronic pain affects almost one fifth of the population of Europe and leads to exorbitant medical expenses as well as extreme suffering. Despite extensive efforts, effective pain treatment has remained elusive. Inadequate understanding of the mechanisms of pain prevents the development of effective therapies. In order to better understand pain mechanisms, a novel integrative approach is needed. This approach should: to investigate the fundamental site of signal detection; the nociceptive terminals and to establish an understanding of the progression from peripheral nociception to central pain perception. Our project aims to integrate analysis at different levels of pain perception in normal and pathological conditions in order to elucidate mechanisms underlying chronic pain. Our approach propose to study pain related mechanisms along somatotopically define neuroaxis of vibrissae-barrel system. Using this unique system where peripheral receptor directly corresponds to its central analyzer, we will first characterize noxious signal detection by single channels in individual nociceptive terminal. We will follow propagation of nociceptive signal and monitor activity-dependent changes in corresponding circuits at trigeminal nuclei, thalamus and cortex. We will study modulation in of synaptic connectivity in the spino-thalamo-cortical pathway in models of chronic pain. This multi-disciplinary project will incorporate ground-breaking imaging techniques and state-of-the-art electrophysiological, histological and behavioural experiments to study pain-related mechanisms at the molecular and cellular levels as well as at the level of neuronal networks and behaviour.
Summary
The worst of evils - pain is one of the main reasons for seeking medical help. Chronic pain affects almost one fifth of the population of Europe and leads to exorbitant medical expenses as well as extreme suffering. Despite extensive efforts, effective pain treatment has remained elusive. Inadequate understanding of the mechanisms of pain prevents the development of effective therapies. In order to better understand pain mechanisms, a novel integrative approach is needed. This approach should: to investigate the fundamental site of signal detection; the nociceptive terminals and to establish an understanding of the progression from peripheral nociception to central pain perception. Our project aims to integrate analysis at different levels of pain perception in normal and pathological conditions in order to elucidate mechanisms underlying chronic pain. Our approach propose to study pain related mechanisms along somatotopically define neuroaxis of vibrissae-barrel system. Using this unique system where peripheral receptor directly corresponds to its central analyzer, we will first characterize noxious signal detection by single channels in individual nociceptive terminal. We will follow propagation of nociceptive signal and monitor activity-dependent changes in corresponding circuits at trigeminal nuclei, thalamus and cortex. We will study modulation in of synaptic connectivity in the spino-thalamo-cortical pathway in models of chronic pain. This multi-disciplinary project will incorporate ground-breaking imaging techniques and state-of-the-art electrophysiological, histological and behavioural experiments to study pain-related mechanisms at the molecular and cellular levels as well as at the level of neuronal networks and behaviour.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-03-01, End date: 2016-02-29
