Project acronym 20SComplexity
Project An integrative approach to uncover the multilevel regulation of 20S proteasome degradation
Researcher (PI) Michal Sharon
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS1, ERC-2014-STG
Summary For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route.
To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation:
Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome.
Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function.
Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach.
Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.
Summary
For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route.
To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation:
Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome.
Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function.
Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach.
Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym ABDESIGN
Project Computational design of novel protein function in antibodies
Researcher (PI) Sarel-Jacob Fleishman
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS1, ERC-2013-StG
Summary We propose to elucidate the structural design principles of naturally occurring antibody complementarity-determining regions (CDRs) and to computationally design novel antibody functions. Antibodies represent the most versatile known system for molecular recognition. Research has yielded many insights into antibody design principles and promising biotechnological and pharmaceutical applications. Still, our understanding of how CDRs encode specific loop conformations lags far behind our understanding of structure-function relationships in non-immunological scaffolds. Thus, design of antibodies from first principles has not been demonstrated. We propose a computational-experimental strategy to address this challenge. We will: (a) characterize the design principles and sequence elements that rigidify antibody CDRs. Natural antibody loops will be subjected to computational modeling, crystallography, and a combined in vitro evolution and deep-sequencing approach to isolate sequence features that rigidify loop backbones; (b) develop a novel computational-design strategy, which uses the >1000 solved structures of antibodies deposited in structure databases to realistically model CDRs and design them to recognize proteins that have not been co-crystallized with antibodies. For example, we will design novel antibodies targeting insulin, for which clinically useful diagnostics are needed. By accessing much larger sequence/structure spaces than are available to natural immune-system repertoires and experimental methods, computational antibody design could produce higher-specificity and higher-affinity binders, even to challenging targets; and (c) develop new strategies to program conformational change in CDRs, generating, e.g., the first allosteric antibodies. These will allow targeting, in principle, of any molecule, potentially revolutionizing how antibodies are generated for research and medicine, providing new insights on the design principles of protein functional sites.
Summary
We propose to elucidate the structural design principles of naturally occurring antibody complementarity-determining regions (CDRs) and to computationally design novel antibody functions. Antibodies represent the most versatile known system for molecular recognition. Research has yielded many insights into antibody design principles and promising biotechnological and pharmaceutical applications. Still, our understanding of how CDRs encode specific loop conformations lags far behind our understanding of structure-function relationships in non-immunological scaffolds. Thus, design of antibodies from first principles has not been demonstrated. We propose a computational-experimental strategy to address this challenge. We will: (a) characterize the design principles and sequence elements that rigidify antibody CDRs. Natural antibody loops will be subjected to computational modeling, crystallography, and a combined in vitro evolution and deep-sequencing approach to isolate sequence features that rigidify loop backbones; (b) develop a novel computational-design strategy, which uses the >1000 solved structures of antibodies deposited in structure databases to realistically model CDRs and design them to recognize proteins that have not been co-crystallized with antibodies. For example, we will design novel antibodies targeting insulin, for which clinically useful diagnostics are needed. By accessing much larger sequence/structure spaces than are available to natural immune-system repertoires and experimental methods, computational antibody design could produce higher-specificity and higher-affinity binders, even to challenging targets; and (c) develop new strategies to program conformational change in CDRs, generating, e.g., the first allosteric antibodies. These will allow targeting, in principle, of any molecule, potentially revolutionizing how antibodies are generated for research and medicine, providing new insights on the design principles of protein functional sites.
Max ERC Funding
1 499 930 €
Duration
Start date: 2013-09-01, End date: 2018-08-31
Project acronym APARTHEID-STOPS
Project Apartheid -- The Global Itinerary: South African Cultural Formations in Transnational Circulation, 1948-1990
Researcher (PI) Louise Bethlehem
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Consolidator Grant (CoG), SH5, ERC-2013-CoG
Summary This proposal proceeds from an anomaly. Apartheid routinely breached the separation that it names. Whereas the South African regime was deeply isolationist in international terms, new research links it to the Cold War and decolonization. Yet this trend does not consider sufficiently that the global contest over the meaning of apartheid and resistance to it occurs on the terrain of culture. My project argues that studying the global circulation of South African cultural formations in the apartheid era provides novel historiographic leverage over Western liberalism during the Cold War. It recasts apartheid as an apparatus of transnational cultural production, turning existing historiography inside out. This study seeks:
• To provide the first systematic account of the deterritorialization of “apartheid”—as political signifier and as apparatus generating circuits of transnational cultural production.
• To analyze these itinerant cultural formations across media and national borders, articulating new intersections.
• To map the itineraries of major South African exiles, where exile is taken to be a system of interlinked circuits of affiliation and cultural production.
• To revise the historiography of states other than South Africa through the lens of deterritorialized apartheid-era formations at their respective destinations.
• To show how apartheid reveals contradictions within Western liberalism during the Cold War, with special reference to racial inequality.
Methodologically, I introduce the model of thick convergence to analyze three periods:
1. Kliptown & Bandung: Novel possibilities, 1948-1960.
2. Sharpeville & Memphis: Drumming up resistance, 1960-1976.
3. From Soweto to Berlin: Spectacle at the barricades, 1976-1990.
Each explores a cultural dominant in the form of texts, soundscapes or photographs. My work stands at the frontier of transnational research, furnishing powerful new insights into why South Africa matters on the stage of global history.
Summary
This proposal proceeds from an anomaly. Apartheid routinely breached the separation that it names. Whereas the South African regime was deeply isolationist in international terms, new research links it to the Cold War and decolonization. Yet this trend does not consider sufficiently that the global contest over the meaning of apartheid and resistance to it occurs on the terrain of culture. My project argues that studying the global circulation of South African cultural formations in the apartheid era provides novel historiographic leverage over Western liberalism during the Cold War. It recasts apartheid as an apparatus of transnational cultural production, turning existing historiography inside out. This study seeks:
• To provide the first systematic account of the deterritorialization of “apartheid”—as political signifier and as apparatus generating circuits of transnational cultural production.
• To analyze these itinerant cultural formations across media and national borders, articulating new intersections.
• To map the itineraries of major South African exiles, where exile is taken to be a system of interlinked circuits of affiliation and cultural production.
• To revise the historiography of states other than South Africa through the lens of deterritorialized apartheid-era formations at their respective destinations.
• To show how apartheid reveals contradictions within Western liberalism during the Cold War, with special reference to racial inequality.
Methodologically, I introduce the model of thick convergence to analyze three periods:
1. Kliptown & Bandung: Novel possibilities, 1948-1960.
2. Sharpeville & Memphis: Drumming up resistance, 1960-1976.
3. From Soweto to Berlin: Spectacle at the barricades, 1976-1990.
Each explores a cultural dominant in the form of texts, soundscapes or photographs. My work stands at the frontier of transnational research, furnishing powerful new insights into why South Africa matters on the stage of global history.
Max ERC Funding
1 861 238 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym BACTERIAL SPORES
Project Investigating the Nature of Bacterial Spores
Researcher (PI) Sigal Ben-Yehuda
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary When triggered by nutrient limitation, the Gram-positive bacterium Bacillus subtilis and its relatives enter a pathway of cellular differentiation culminating in the formation of a dormant cell type called a spore, the most resilient cell type known. Bacterial spores can survive for long periods of time and are able to endure extremes of heat, radiation and chemical assault. Remarkably, dormant spores can rapidly convert back to actively growing cells by a process called germination. Consequently, spore forming bacteria, including dangerous pathogens, (such as C. botulinum and B. anthracis) are highly resistant to antibacterial treatments and difficult to eradicate. Despite significant advances in our understanding of the process of spore formation, little is known about the nature of the mature spore. It is unrevealed how dormancy is maintained within the spore and how it is ceased, as the organization and the dynamics of the spore macromolecules remain obscure. The unusual biochemical and biophysical characteristics of the dormant spore make it a challenging biological system to investigate using conventional methods, and thus set the need to develop innovative approaches to study spore biology. We propose to explore the nature of spores by using B. subtilis as a primary experimental system. We intend to: (1) define the architecture of the spore chromosome, (2) track the complexity and fate of mRNA and protein molecules during sporulation, dormancy and germination, (3) revisit the basic notion of the spore dormancy (is it metabolically inert?), (4) compare the characteristics of bacilli spores from diverse ecophysiological groups, (5) investigate the features of spores belonging to distant bacterial genera, (6) generate an integrative database that categorizes the molecular features of spores. Our study will provide original insights and introduce novel concepts to the field of spore biology and may help devise innovative ways to combat spore forming pathogens.
Summary
When triggered by nutrient limitation, the Gram-positive bacterium Bacillus subtilis and its relatives enter a pathway of cellular differentiation culminating in the formation of a dormant cell type called a spore, the most resilient cell type known. Bacterial spores can survive for long periods of time and are able to endure extremes of heat, radiation and chemical assault. Remarkably, dormant spores can rapidly convert back to actively growing cells by a process called germination. Consequently, spore forming bacteria, including dangerous pathogens, (such as C. botulinum and B. anthracis) are highly resistant to antibacterial treatments and difficult to eradicate. Despite significant advances in our understanding of the process of spore formation, little is known about the nature of the mature spore. It is unrevealed how dormancy is maintained within the spore and how it is ceased, as the organization and the dynamics of the spore macromolecules remain obscure. The unusual biochemical and biophysical characteristics of the dormant spore make it a challenging biological system to investigate using conventional methods, and thus set the need to develop innovative approaches to study spore biology. We propose to explore the nature of spores by using B. subtilis as a primary experimental system. We intend to: (1) define the architecture of the spore chromosome, (2) track the complexity and fate of mRNA and protein molecules during sporulation, dormancy and germination, (3) revisit the basic notion of the spore dormancy (is it metabolically inert?), (4) compare the characteristics of bacilli spores from diverse ecophysiological groups, (5) investigate the features of spores belonging to distant bacterial genera, (6) generate an integrative database that categorizes the molecular features of spores. Our study will provide original insights and introduce novel concepts to the field of spore biology and may help devise innovative ways to combat spore forming pathogens.
Max ERC Funding
1 630 000 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
Project acronym BeyondtheElite
Project Beyond the Elite: Jewish Daily Life in Medieval Europe
Researcher (PI) Elisheva Baumgarten
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Consolidator Grant (CoG), SH6, ERC-2015-CoG
Summary The two fundamental challenges of this project are the integration of medieval Jewries and their histories within the framework of European history without undermining their distinct communal status and the creation of a history of everyday medieval Jewish life that includes those who were not part of the learned elite. The study will focus on the Jewish communities of northern Europe (roughly modern Germany, northern France and England) from 1100-1350. From the mid-thirteenth century these medieval Jewish communities were subject to growing persecution. The approaches proposed to access daily praxis seek to highlight tangible dimensions of religious life rather than the more common study of ideologies to date. This task is complex because the extant sources in Hebrew as well as those in Latin and vernacular were written by the learned elite and will require a broad survey of multiple textual and material sources.
Four main strands will be examined and combined:
1. An outline of the strata of Jewish society, better defining the elites and other groups.
2. A study of select communal and familial spaces such as the house, the synagogue, the market place have yet to be examined as social spaces.
3. Ritual and urban rhythms especially the annual cycle, connecting between Jewish and Christian environments.
4. Material culture, as objects were used by Jews and Christians alike.
Aspects of material culture, the physical environment and urban rhythms are often described as “neutral” yet will be mined to demonstrate how they exemplified difference while being simultaneously ubiquitous in local cultures. The deterioration of relations between Jews and Christians will provide a gauge for examining change during this period. The final stage of the project will include comparative case studies of other Jewish communities. I expect my findings will inform scholars of medieval culture at large and promote comparative methodologies for studying other minority ethnic groups
Summary
The two fundamental challenges of this project are the integration of medieval Jewries and their histories within the framework of European history without undermining their distinct communal status and the creation of a history of everyday medieval Jewish life that includes those who were not part of the learned elite. The study will focus on the Jewish communities of northern Europe (roughly modern Germany, northern France and England) from 1100-1350. From the mid-thirteenth century these medieval Jewish communities were subject to growing persecution. The approaches proposed to access daily praxis seek to highlight tangible dimensions of religious life rather than the more common study of ideologies to date. This task is complex because the extant sources in Hebrew as well as those in Latin and vernacular were written by the learned elite and will require a broad survey of multiple textual and material sources.
Four main strands will be examined and combined:
1. An outline of the strata of Jewish society, better defining the elites and other groups.
2. A study of select communal and familial spaces such as the house, the synagogue, the market place have yet to be examined as social spaces.
3. Ritual and urban rhythms especially the annual cycle, connecting between Jewish and Christian environments.
4. Material culture, as objects were used by Jews and Christians alike.
Aspects of material culture, the physical environment and urban rhythms are often described as “neutral” yet will be mined to demonstrate how they exemplified difference while being simultaneously ubiquitous in local cultures. The deterioration of relations between Jews and Christians will provide a gauge for examining change during this period. The final stage of the project will include comparative case studies of other Jewish communities. I expect my findings will inform scholars of medieval culture at large and promote comparative methodologies for studying other minority ethnic groups
Max ERC Funding
1 941 688 €
Duration
Start date: 2016-11-01, End date: 2021-10-31
Project acronym CBTC
Project The Resurgence in Wage Inequality and Technological Change: A New Approach
Researcher (PI) Tali Kristal
Host Institution (HI) UNIVERSITY OF HAIFA
Call Details Starting Grant (StG), SH2, ERC-2015-STG
Summary Social-science explanations for rising wage inequality have reached a dead end. Most economists argue that computerization has been primarily responsible, while on the other side of the argument are sociologists and political scientists who stress the role of political forces in the evolution process of wages. I would like to use my knowledge and experience to come up with an original theory on the complex dynamics between technology and politics in order to solve two unsettled questions regarding the role of computerization in rising wage inequality: First, how can computerization, which diffused simultaneously in rich countries, explain the divergent inequality trends in Europe and the United States? Second, what are the mechanisms behind the well-known observed positive correlation between computers and earnings?
To answer the first question, I develop a new institutional agenda stating that politics, broadly defined, mitigates the effects of technological change on wages by stimulating norms of fair pay and equity. To answer the second question, I propose a truly novel perspective that conceptualizes the earnings advantage that derives from computerization around access to and control of information on the production process. Capitalizing on this new perspective, I develop a new approach to measuring computerization to capture the form of workers’ interaction with computers at work, and build a research strategy for analysing the effect of computerization on wages across countries and workplaces, and over time.
This research project challenges the common understanding of technology’s role in producing economic inequality, and would thereby significantly impact all of the abovementioned disciplines, which are debating over the upswing in wage inequality, as well as public policy, which discusses what should be done to confront the resurgence of income inequality.
Summary
Social-science explanations for rising wage inequality have reached a dead end. Most economists argue that computerization has been primarily responsible, while on the other side of the argument are sociologists and political scientists who stress the role of political forces in the evolution process of wages. I would like to use my knowledge and experience to come up with an original theory on the complex dynamics between technology and politics in order to solve two unsettled questions regarding the role of computerization in rising wage inequality: First, how can computerization, which diffused simultaneously in rich countries, explain the divergent inequality trends in Europe and the United States? Second, what are the mechanisms behind the well-known observed positive correlation between computers and earnings?
To answer the first question, I develop a new institutional agenda stating that politics, broadly defined, mitigates the effects of technological change on wages by stimulating norms of fair pay and equity. To answer the second question, I propose a truly novel perspective that conceptualizes the earnings advantage that derives from computerization around access to and control of information on the production process. Capitalizing on this new perspective, I develop a new approach to measuring computerization to capture the form of workers’ interaction with computers at work, and build a research strategy for analysing the effect of computerization on wages across countries and workplaces, and over time.
This research project challenges the common understanding of technology’s role in producing economic inequality, and would thereby significantly impact all of the abovementioned disciplines, which are debating over the upswing in wage inequality, as well as public policy, which discusses what should be done to confront the resurgence of income inequality.
Max ERC Funding
1 495 091 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym CELLREPROGRAMMING
Project Uncovering the Mechanisms of Epigenetic Reprogramming of Pluripotent and Somatic Cell States
Researcher (PI) Yaqub Hanna
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS3, ERC-2011-StG_20101109
Summary The generation of animals by nuclear transfer demonstrated that the epigenetic state of somatic cells could be reset to an embryonic state, capable of directing the development of a new organism. The nuclear cloning technology is of interest for transplantation medicine, but any application is hampered by the inefficiency and ethical problems. A breakthrough solving these issues has been the in vitro derivation of reprogrammed Induced Pluripotent Stem “iPS” cells by the ectopic expression of defined transcription factors in somatic cells. iPS cells recapitulate all defining features of embryo-derived pluripotent stem cells, including the ability to differentiate into all somatic cell types. Further, recent publications have demonstrated the ability to directly trans-differentiate somatic cell types by ectopic expression of lineage specification factors. Thus, it is becoming increasingly clear that an ultimate goal in the stem cell field is to enable scientists to have the power to safely manipulate somatic cells by “reprogramming” their behavior at will. However, to frame this challenge, we must understand the basic mechanisms underlying the generation of reprogrammed cells in parallel to designing strategies for their medical application and their use in human disease specific research. In this ERC Starting Grant proposal, I describe comprehensive lines of experimentation that I plan to conduct in my new lab scheduled to open in April 2011 at the Weizmann Institute of Science. We will utilize exacting transgenic mammalian models and high throughput sequencing and genomic screening tools for in depth characterization of the molecular “rules” of rewiring the epigenome of somatic and pluripotent cell states. The proposed research endeavors will not only contribute to the development of safer strategies for cell reprogramming, but will also help decipher how diverse gene expression programs lead to cellular specification during normal development.
Summary
The generation of animals by nuclear transfer demonstrated that the epigenetic state of somatic cells could be reset to an embryonic state, capable of directing the development of a new organism. The nuclear cloning technology is of interest for transplantation medicine, but any application is hampered by the inefficiency and ethical problems. A breakthrough solving these issues has been the in vitro derivation of reprogrammed Induced Pluripotent Stem “iPS” cells by the ectopic expression of defined transcription factors in somatic cells. iPS cells recapitulate all defining features of embryo-derived pluripotent stem cells, including the ability to differentiate into all somatic cell types. Further, recent publications have demonstrated the ability to directly trans-differentiate somatic cell types by ectopic expression of lineage specification factors. Thus, it is becoming increasingly clear that an ultimate goal in the stem cell field is to enable scientists to have the power to safely manipulate somatic cells by “reprogramming” their behavior at will. However, to frame this challenge, we must understand the basic mechanisms underlying the generation of reprogrammed cells in parallel to designing strategies for their medical application and their use in human disease specific research. In this ERC Starting Grant proposal, I describe comprehensive lines of experimentation that I plan to conduct in my new lab scheduled to open in April 2011 at the Weizmann Institute of Science. We will utilize exacting transgenic mammalian models and high throughput sequencing and genomic screening tools for in depth characterization of the molecular “rules” of rewiring the epigenome of somatic and pluripotent cell states. The proposed research endeavors will not only contribute to the development of safer strategies for cell reprogramming, but will also help decipher how diverse gene expression programs lead to cellular specification during normal development.
Max ERC Funding
1 960 000 €
Duration
Start date: 2011-11-01, End date: 2016-10-31
Project acronym ChangeBehavNeuro
Project Novel Mechanism of Behavioural Change
Researcher (PI) Tom SCHONBERG
Host Institution (HI) TEL AVIV UNIVERSITY
Call Details Starting Grant (StG), SH4, ERC-2016-STG
Summary Understanding how values of different options that lead to choice are represented in the brain is a basic scientific question with far reaching implications. I recently showed that by the mere-association of a cue and a button press we could influence preferences of snack food items up to two months following a single training session lasting less than an hour. This novel behavioural change manipulation cannot be explained by any of the current learning theories, as external reinforcement was not used in the process, nor was the context of the decision changed. Current choice theories focus on goal directed behaviours where the value of the outcome guides choice, versus habit-based behaviours where an action is repeated up to the point that the value of the outcome no longer guides choice. However, in this novel task training via the involvement of low-level visual, auditory and motor mechanisms influenced high-level choice behaviour. Thus, the far-reaching goal of this project is to study the mechanism, by which low-level sensory, perceptual and motor neural processes underlie value representation and change in the human brain even in the absence of external reinforcement. I will use behavioural, eye-gaze and functional MRI experiments to test how low-level features influence the neural representation of value. I will then test how they interact with the known striatal representation of reinforced behavioural change, which has been the main focus of research thus far. Finally, I will address the basic question of dynamic neural plasticity and if neural signatures during training predict long term success of sustained behavioural change. This research aims at a paradigmatic shift in the field of learning and decision-making, leading to the development of novel interventions with potential societal impact of helping those suffering from health-injuring behaviours such as addictions, eating or mood disorders, all in need of a long lasting behavioural change.
Summary
Understanding how values of different options that lead to choice are represented in the brain is a basic scientific question with far reaching implications. I recently showed that by the mere-association of a cue and a button press we could influence preferences of snack food items up to two months following a single training session lasting less than an hour. This novel behavioural change manipulation cannot be explained by any of the current learning theories, as external reinforcement was not used in the process, nor was the context of the decision changed. Current choice theories focus on goal directed behaviours where the value of the outcome guides choice, versus habit-based behaviours where an action is repeated up to the point that the value of the outcome no longer guides choice. However, in this novel task training via the involvement of low-level visual, auditory and motor mechanisms influenced high-level choice behaviour. Thus, the far-reaching goal of this project is to study the mechanism, by which low-level sensory, perceptual and motor neural processes underlie value representation and change in the human brain even in the absence of external reinforcement. I will use behavioural, eye-gaze and functional MRI experiments to test how low-level features influence the neural representation of value. I will then test how they interact with the known striatal representation of reinforced behavioural change, which has been the main focus of research thus far. Finally, I will address the basic question of dynamic neural plasticity and if neural signatures during training predict long term success of sustained behavioural change. This research aims at a paradigmatic shift in the field of learning and decision-making, leading to the development of novel interventions with potential societal impact of helping those suffering from health-injuring behaviours such as addictions, eating or mood disorders, all in need of a long lasting behavioural change.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym CIRCOMMUNICATION
Project Deciphering molecular pathways of circadian clock communication
Researcher (PI) gad ASHER
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Consolidator Grant (CoG), LS1, ERC-2017-COG
Summary The overarching objective of this interdisciplinary project is to elucidate mechanisms through which billions of individual clocks in the body communicate with each other and tick in harmony. The mammalian circadian timing system consists of a master clock in the brain and subsidiary oscillators in almost every cell of the body. Since these clocks anticipate environmental changes and function together to orchestrate daily physiology and behavior their temporal synchronization is critical.
Our recent finding that oxygen serves as a resetting cue for circadian clocks points towards the unprecedented involvement of blood gases as time signals. We will apply cutting edge continuous physiological measurements in freely moving animals, alongside biochemical/molecular biology approaches and advanced cell culture setup to determine the molecular role of oxygen, carbon dioxide and pH in circadian clock communication and function.
The intricate nature of the mammalian circadian system demands the presence of communication mechanisms between clocks throughout the body at multiple levels. While previous studies primarily addressed the role of the master clock in resetting peripheral clocks, our knowledge regarding the communication among clocks between and within peripheral organs is rudimentary. We will reconstruct the mammalian circadian system from the bottom up, sequentially restoring clocks in peripheral tissues of a non-rhythmic animal to (i) obtain a system-view of the peripheral circadian communication network; and (ii) study novel tissue-derived circadian communication mechanisms.
This integrative proposal addresses fundamental aspects of circadian biology. It is expected to unravel the circadian communication network and shed light on how billions of clocks in the body function in unison. Its impact extends beyond circadian rhythms and bears great potential for research on communication between cells/tissues in various fields of biology.
Summary
The overarching objective of this interdisciplinary project is to elucidate mechanisms through which billions of individual clocks in the body communicate with each other and tick in harmony. The mammalian circadian timing system consists of a master clock in the brain and subsidiary oscillators in almost every cell of the body. Since these clocks anticipate environmental changes and function together to orchestrate daily physiology and behavior their temporal synchronization is critical.
Our recent finding that oxygen serves as a resetting cue for circadian clocks points towards the unprecedented involvement of blood gases as time signals. We will apply cutting edge continuous physiological measurements in freely moving animals, alongside biochemical/molecular biology approaches and advanced cell culture setup to determine the molecular role of oxygen, carbon dioxide and pH in circadian clock communication and function.
The intricate nature of the mammalian circadian system demands the presence of communication mechanisms between clocks throughout the body at multiple levels. While previous studies primarily addressed the role of the master clock in resetting peripheral clocks, our knowledge regarding the communication among clocks between and within peripheral organs is rudimentary. We will reconstruct the mammalian circadian system from the bottom up, sequentially restoring clocks in peripheral tissues of a non-rhythmic animal to (i) obtain a system-view of the peripheral circadian communication network; and (ii) study novel tissue-derived circadian communication mechanisms.
This integrative proposal addresses fundamental aspects of circadian biology. It is expected to unravel the circadian communication network and shed light on how billions of clocks in the body function in unison. Its impact extends beyond circadian rhythms and bears great potential for research on communication between cells/tissues in various fields of biology.
Max ERC Funding
1 999 945 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym DEADSEA_ECO
Project Modelling Anthropocene Trophic Cascades of the Judean Desert Ecosystem: A Hidden Dimension in the History of Human-Environment Interactions
Researcher (PI) Nimrod MAROM
Host Institution (HI) UNIVERSITY OF HAIFA
Call Details Starting Grant (StG), SH6, ERC-2018-STG
Summary This project aims to explore the effects of human settlement intensity on desert ecological community structure, focusing on the hitherto unstudied phenomenon of trophic cascades in antiquity. Its key research question is whether human-induced changes in arid land biodiversity can feedback to affect natural resources important for human subsistence, such as pasture and wood. The role of such feedback effects in ecological systems is increasingly acknowledged in recent years in the biological literature but has not been addressed in the study of human past. The research question will be approached using bioarchaeological methods applied to the uniquely-preserved material record from the middle and late Holocene settlement sequence (approximately 4,500 BCE to 700 CE) of the Dead Sea Ein Gedi Oasis, and to the contemporary palaeontological assemblages from caves located in the surrounding Judean Desert. The proposed research is expected to bridge between aspects of current thinking on ecosystem dynamics and the study of human past by exploring the role of trophic cascades as an invisible dimension of Anthropocene life in marginal environments. The study of the history of human impact on such environments is important to resource management planning across a rapidly expanding ecological frontier on Earth, as climate deterioration brings more people in contact with life-sustaining and sensitive arid land ecosystems.
Summary
This project aims to explore the effects of human settlement intensity on desert ecological community structure, focusing on the hitherto unstudied phenomenon of trophic cascades in antiquity. Its key research question is whether human-induced changes in arid land biodiversity can feedback to affect natural resources important for human subsistence, such as pasture and wood. The role of such feedback effects in ecological systems is increasingly acknowledged in recent years in the biological literature but has not been addressed in the study of human past. The research question will be approached using bioarchaeological methods applied to the uniquely-preserved material record from the middle and late Holocene settlement sequence (approximately 4,500 BCE to 700 CE) of the Dead Sea Ein Gedi Oasis, and to the contemporary palaeontological assemblages from caves located in the surrounding Judean Desert. The proposed research is expected to bridge between aspects of current thinking on ecosystem dynamics and the study of human past by exploring the role of trophic cascades as an invisible dimension of Anthropocene life in marginal environments. The study of the history of human impact on such environments is important to resource management planning across a rapidly expanding ecological frontier on Earth, as climate deterioration brings more people in contact with life-sustaining and sensitive arid land ecosystems.
Max ERC Funding
1 499 563 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
