Project acronym ACTMECH
Project Emergent Active Mechanical Behaviour of the Actomyosin Cell Cortex
Researcher (PI) Stephan Wolfgang Grill
Host Institution (HI) TECHNISCHE UNIVERSITAET DRESDEN
Call Details Starting Grant (StG), LS3, ERC-2011-StG_20101109
Summary The cell cortex is a highly dynamic layer of crosslinked actin filaments and myosin molecular motors beneath the cell membrane. It plays a central role in large scale rearrangements that occur inside cells. Many molecular mechanisms contribute to cortex structure and dynamics. However, cell scale physical properties of the cortex are difficult to grasp. This is problematic because for large scale rearrangements inside a cell, such as coherent flow of the cell cortex, it is the cell scale emergent properties that are important for the realization of such events. I will investigate how the actomyosin cytoskeleton behaves at a coarse grained and cellular scale, and will study how this emergent active behaviour is influenced by molecular mechanisms. We will study the cell cortex in the one cell stage C. elegans embryo, which undergoes large scale cortical flow during polarization and cytokinesis. We will combine theory and experiment. We will characterize cortex structure and dynamics with biophysical techniques such as cortical laser ablation and quantitative photobleaching experiments. We will develop and employ novel theoretical approaches to describe the cell scale mechanical behaviour in terms of an active complex fluid. We will utilize genetic approaches to understand how these emergent mechanical properties are influenced by molecular activities. A central goal is to arrive at a coarse grained description of the cortex that can predict future dynamic behaviour from the past structure, which is conceptually similar to how weather forecasting is accomplished. To date, systematic approaches to link molecular scale physical mechanisms to those on cellular scales are missing. This work will open new opportunities for cell biological and cell biophysical research, by providing a methodological approach for bridging scales, for studying emergent and large-scale active mechanical behaviours and linking them to molecular mechanisms.
Summary
The cell cortex is a highly dynamic layer of crosslinked actin filaments and myosin molecular motors beneath the cell membrane. It plays a central role in large scale rearrangements that occur inside cells. Many molecular mechanisms contribute to cortex structure and dynamics. However, cell scale physical properties of the cortex are difficult to grasp. This is problematic because for large scale rearrangements inside a cell, such as coherent flow of the cell cortex, it is the cell scale emergent properties that are important for the realization of such events. I will investigate how the actomyosin cytoskeleton behaves at a coarse grained and cellular scale, and will study how this emergent active behaviour is influenced by molecular mechanisms. We will study the cell cortex in the one cell stage C. elegans embryo, which undergoes large scale cortical flow during polarization and cytokinesis. We will combine theory and experiment. We will characterize cortex structure and dynamics with biophysical techniques such as cortical laser ablation and quantitative photobleaching experiments. We will develop and employ novel theoretical approaches to describe the cell scale mechanical behaviour in terms of an active complex fluid. We will utilize genetic approaches to understand how these emergent mechanical properties are influenced by molecular activities. A central goal is to arrive at a coarse grained description of the cortex that can predict future dynamic behaviour from the past structure, which is conceptually similar to how weather forecasting is accomplished. To date, systematic approaches to link molecular scale physical mechanisms to those on cellular scales are missing. This work will open new opportunities for cell biological and cell biophysical research, by providing a methodological approach for bridging scales, for studying emergent and large-scale active mechanical behaviours and linking them to molecular mechanisms.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-12-01, End date: 2017-08-31
Project acronym AR.C.H.I.VES
Project A comparative history of archives in late medieval and early modern Italy
Researcher (PI) Filippo Luciano Carlo De Vivo
Host Institution (HI) BIRKBECK COLLEGE - UNIVERSITY OF LONDON
Call Details Starting Grant (StG), SH6, ERC-2011-StG_20101124
Summary Most historians work in archives, but generally have not made archives into their primary object of research. While we tend to be preoccupied by documentary loss, what is striking is the sheer amount of paperwork preserved over the centuries. We need to study the reasons for this preservation.
This project wishes to study the history of the archives and of the chanceries that oversaw their production storage and organization in late medieval and early modern Italy: essentially from the creation of the first chanceries in city-states in the late twelfth century to the opening of the Archivi di Stato that, after the ancient states’ dissolution, preserved documents as tools for scholarship rather than administration. Because of its fragmented political history, concentrating on Italy means having access to the archives of a wide variety of regimes; in turn, as institutions pursuing similar functions, archives lend themselves to comparison and therefore such research may help us overcome the traditional disconnectedness in the study of Italy’s past.
The project proposes to break significantly new ground, first, by adopting a comparative approach through the in-depth analysis of seven case studies and, second, by contextualising the study of archives away from institutional history in a wider social and cultural context, by focusing on six themes researched in six successive phases: 1) the political role of archives, and the efforts devoted by governments to their development; 2) their organization, subdivisions, referencing systems; 3) the material culture of documents and physical repositories as well as spatial locations; 4) the social characteristiscs of the staff; 5) the archives’ place in society, including their access and misuse; 6) their use by historians. As implied in the choice of these themes, the project is deliberately interdisciplinary, and aims at the mutually beneficial exchange between archivists, social, political cultural and art historians.
Summary
Most historians work in archives, but generally have not made archives into their primary object of research. While we tend to be preoccupied by documentary loss, what is striking is the sheer amount of paperwork preserved over the centuries. We need to study the reasons for this preservation.
This project wishes to study the history of the archives and of the chanceries that oversaw their production storage and organization in late medieval and early modern Italy: essentially from the creation of the first chanceries in city-states in the late twelfth century to the opening of the Archivi di Stato that, after the ancient states’ dissolution, preserved documents as tools for scholarship rather than administration. Because of its fragmented political history, concentrating on Italy means having access to the archives of a wide variety of regimes; in turn, as institutions pursuing similar functions, archives lend themselves to comparison and therefore such research may help us overcome the traditional disconnectedness in the study of Italy’s past.
The project proposes to break significantly new ground, first, by adopting a comparative approach through the in-depth analysis of seven case studies and, second, by contextualising the study of archives away from institutional history in a wider social and cultural context, by focusing on six themes researched in six successive phases: 1) the political role of archives, and the efforts devoted by governments to their development; 2) their organization, subdivisions, referencing systems; 3) the material culture of documents and physical repositories as well as spatial locations; 4) the social characteristiscs of the staff; 5) the archives’ place in society, including their access and misuse; 6) their use by historians. As implied in the choice of these themes, the project is deliberately interdisciplinary, and aims at the mutually beneficial exchange between archivists, social, political cultural and art historians.
Max ERC Funding
1 107 070 €
Duration
Start date: 2012-02-01, End date: 2016-07-31
Project acronym ARABCOMMAPH
Project Arabic Commentaries on the Hippocratic Aphorisms
Researcher (PI) Peter Ernst Pormann
Host Institution (HI) THE UNIVERSITY OF MANCHESTER
Call Details Starting Grant (StG), SH6, ERC-2011-StG_20101124
Summary The Hippocratic Aphorisms have exerted a singular influence over generations of physicians both in the East and in the West. Galen (d. c. 216) produced an extensive commentary on this text, as did other medical authors writing in Greek, Latin, Arabic, and Hebrew. The Arabic tradition is particularly rich, with more than a dozen commentaries extant in over a hundred manuscripts. These Arabic commentaries did not merely contain scholastic debates, but constituted important venues for innovation and change. Moreover, they impacted on medical practice, as the Aphorisms were so popular that both doctors and their patients knew them by heart. Despite their importance for medical theory and practice, previous scholarship on them has barely scratched the surface. Put succinctly, the present project breaks new ground by conducting an in-depth study of this tradition through a highly innovative methodology: it approaches the available evidence as a corpus, to be constituted electronically, and to be analysed in an interdisciplinary way.
We propose to survey the manuscript tradition of the Arabic commentaries on the Hippocratic Aphorisms, beginning with Ḥunayn ibn ʾIsḥāq’s Arabic translation of Galen’s commentary. On the basis of this philological survey that will employ a new approach to stemmatics, we shall produce provisional electronic XML editions of the commentaries. These texts will constitute the corpus, some 600,000 words long, that we shall investigate through the latest IT tools to address a set of interdisciplinary problems: textual criticism of the Greek sources; Graeco-Arabic translation technique; methods of quotation; hermeneutic procedures; development of medical theory; medical practice; and social history of medicine. Both in approach and scope, the project will bring about a paradigm shift in our study of exegetical cultures in Arabic, and the role that commentaries played in the transmission and transformation of scientific knowledge.
Summary
The Hippocratic Aphorisms have exerted a singular influence over generations of physicians both in the East and in the West. Galen (d. c. 216) produced an extensive commentary on this text, as did other medical authors writing in Greek, Latin, Arabic, and Hebrew. The Arabic tradition is particularly rich, with more than a dozen commentaries extant in over a hundred manuscripts. These Arabic commentaries did not merely contain scholastic debates, but constituted important venues for innovation and change. Moreover, they impacted on medical practice, as the Aphorisms were so popular that both doctors and their patients knew them by heart. Despite their importance for medical theory and practice, previous scholarship on them has barely scratched the surface. Put succinctly, the present project breaks new ground by conducting an in-depth study of this tradition through a highly innovative methodology: it approaches the available evidence as a corpus, to be constituted electronically, and to be analysed in an interdisciplinary way.
We propose to survey the manuscript tradition of the Arabic commentaries on the Hippocratic Aphorisms, beginning with Ḥunayn ibn ʾIsḥāq’s Arabic translation of Galen’s commentary. On the basis of this philological survey that will employ a new approach to stemmatics, we shall produce provisional electronic XML editions of the commentaries. These texts will constitute the corpus, some 600,000 words long, that we shall investigate through the latest IT tools to address a set of interdisciplinary problems: textual criticism of the Greek sources; Graeco-Arabic translation technique; methods of quotation; hermeneutic procedures; development of medical theory; medical practice; and social history of medicine. Both in approach and scope, the project will bring about a paradigm shift in our study of exegetical cultures in Arabic, and the role that commentaries played in the transmission and transformation of scientific knowledge.
Max ERC Funding
1 499 968 €
Duration
Start date: 2012-02-01, End date: 2017-07-31
Project acronym BABE
Project Bodies across borders: oral and visual memory in Europe and beyond
Researcher (PI) Luisella Passerini
Host Institution (HI) EUROPEAN UNIVERSITY INSTITUTE
Call Details Advanced Grant (AdG), SH6, ERC-2011-ADG_20110406
Summary This project intends to study intercultural connections in contemporary Europe, engaging both native and ‘new’ Europeans. These connections are woven through the faculties of embodied subjects – memory, visuality and mobility – and concern the movement of people, ideas and images across the borders of European nation-states. These faculties are connected with that of affect, an increasingly important concept in history and the social sciences. Memory will be understood not only as oral or direct memory, but also as cultural memory, embodied in various cultural products. Our study aims to understand new forms of European identity, as these develop in an increasingly diasporic world. Europe today is not only a key site of immigration, after having been for centuries an area of emigration, but also a crucial point of arrival in a global network designed by mobile human beings.
Three parts will make up the project. The first will engage with bodies, their gendered dimension, performative capacities and connection to place. It will explore the ways certain bodies are ‘emplaced’ as ‘European’, while others are marked as alien, and contrast these discourses with the counter-narratives by visual artists. The second part will extend further the reflection on the role of the visual arts in challenging an emergent ‘Fortress Europe’ but also in re-imagining the memory of European colonialism. The work of some key artists will be shown to students in Italy and the Netherlands, both recent migrants and ‘natives’, creating an ‘induced reception’. The final part of the project will look at alternative imaginations of Europe, investigating the oral memories and ‘mental maps’ created by two migrant communities in Europe: from Peru and from the Horn of Africa.
Examining the heterogeneous micro-productions of mobility – whether ‘real’ or imagined/envisioned – will thus yield important lessons for the historical understanding of inclusion and exclusion in today’s Europe.
Summary
This project intends to study intercultural connections in contemporary Europe, engaging both native and ‘new’ Europeans. These connections are woven through the faculties of embodied subjects – memory, visuality and mobility – and concern the movement of people, ideas and images across the borders of European nation-states. These faculties are connected with that of affect, an increasingly important concept in history and the social sciences. Memory will be understood not only as oral or direct memory, but also as cultural memory, embodied in various cultural products. Our study aims to understand new forms of European identity, as these develop in an increasingly diasporic world. Europe today is not only a key site of immigration, after having been for centuries an area of emigration, but also a crucial point of arrival in a global network designed by mobile human beings.
Three parts will make up the project. The first will engage with bodies, their gendered dimension, performative capacities and connection to place. It will explore the ways certain bodies are ‘emplaced’ as ‘European’, while others are marked as alien, and contrast these discourses with the counter-narratives by visual artists. The second part will extend further the reflection on the role of the visual arts in challenging an emergent ‘Fortress Europe’ but also in re-imagining the memory of European colonialism. The work of some key artists will be shown to students in Italy and the Netherlands, both recent migrants and ‘natives’, creating an ‘induced reception’. The final part of the project will look at alternative imaginations of Europe, investigating the oral memories and ‘mental maps’ created by two migrant communities in Europe: from Peru and from the Horn of Africa.
Examining the heterogeneous micro-productions of mobility – whether ‘real’ or imagined/envisioned – will thus yield important lessons for the historical understanding of inclusion and exclusion in today’s Europe.
Max ERC Funding
1 488 501 €
Duration
Start date: 2013-06-01, End date: 2018-05-31
Project acronym Boom & Bust Cycles
Project Boom and Bust Cycles in Asset Prices: Real Implications and Monetary Policy Options
Researcher (PI) Klaus Adam
Host Institution (HI) UNIVERSITAET MANNHEIM
Call Details Starting Grant (StG), SH1, ERC-2011-StG_20101124
Summary I seek increasing our understanding of the origin of asset price booms and bust cycles and propose constructing structural dynamic equilibrium models that allow formalizing their interaction with the dynamics of consumption, hours worked, the current account, stock market trading activity, and monetary policy. For this purpose I propose developing macroeconomic models that relax the assumption of common knowledge of beliefs and preferences, incorporating instead subjective beliefs and learning about market behavior. These features allow for sustained deviations of asset prices from fundamentals in a setting where all agents behave individually rational.
The first research project derives the derivative price implications of asset price models with learning agents and determines the limits to arbitrage required so that learning models are consistent with the existence of only weak incentives for improving forecasts and beliefs. The second project introduces housing, collateral constraints and open economy features into existing asset pricing models under learning to explain a range of cross-sectional facts about the behavior of the current account that have been observed in the recent housing boom and bust cycle. The third project constructs quantitatively plausible macro asset pricing models that can explain the dynamics of consumption and hours worked jointly with the occurrence of asset price boom and busts cycles. The forth project develops a set of monetary policy models allowing to study the interaction between monetary policies, the real economy and asset prices, and determines how monetary policy should optimally react to asset price movements. The last project explains the aggregate trading patterns on stock exchanges over boom and bust cycles and improves our understanding of the forces supporting the large cross-sectional heterogeneity in return expectations revealed in survey data.
Summary
I seek increasing our understanding of the origin of asset price booms and bust cycles and propose constructing structural dynamic equilibrium models that allow formalizing their interaction with the dynamics of consumption, hours worked, the current account, stock market trading activity, and monetary policy. For this purpose I propose developing macroeconomic models that relax the assumption of common knowledge of beliefs and preferences, incorporating instead subjective beliefs and learning about market behavior. These features allow for sustained deviations of asset prices from fundamentals in a setting where all agents behave individually rational.
The first research project derives the derivative price implications of asset price models with learning agents and determines the limits to arbitrage required so that learning models are consistent with the existence of only weak incentives for improving forecasts and beliefs. The second project introduces housing, collateral constraints and open economy features into existing asset pricing models under learning to explain a range of cross-sectional facts about the behavior of the current account that have been observed in the recent housing boom and bust cycle. The third project constructs quantitatively plausible macro asset pricing models that can explain the dynamics of consumption and hours worked jointly with the occurrence of asset price boom and busts cycles. The forth project develops a set of monetary policy models allowing to study the interaction between monetary policies, the real economy and asset prices, and determines how monetary policy should optimally react to asset price movements. The last project explains the aggregate trading patterns on stock exchanges over boom and bust cycles and improves our understanding of the forces supporting the large cross-sectional heterogeneity in return expectations revealed in survey data.
Max ERC Funding
769 440 €
Duration
Start date: 2011-09-01, End date: 2017-04-30
Project acronym BRAINEVODEVO
Project A Neuron Type Atlas of the Annelid Brain: Development and Evolution of Chemosensory-Motor Circuits
Researcher (PI) Detlev Arendt
Host Institution (HI) EUROPEAN MOLECULAR BIOLOGY LABORATORY
Call Details Advanced Grant (AdG), LS3, ERC-2011-ADG_20110310
Summary Neural circuits, composed of interconnected neurons, represent the basic unit of the nervous system. One way to understand the highly complex arrangement of cross-talking, serial and parallel circuits is to resolve its developmental and evolutionary emergence. The rationale of the research proposal presented here is to elucidate the complex circuitry of the vertebrate and insect forebrain by comparison to the much simpler and evolutionary ancient “connectome” of the marine annelid Platynereis dumerilii. We will build a unique resource, the Platynereis Neuron Type Atlas, combining, for the first time, neuronal morphologies, axonal projections, cellular expression profiling and developmental lineage for an entire bilaterian brain. We will focus on five days old larvae when most adult neuron types are already present in small number and large part of the axonal scaffold in place.
Building on the Neuron Type Atlas, the second part of the proposal envisages the functional dissection of the Platynereis chemosensory-motor forebrain circuits. A newly developed microfluidics behavioural assay system, together with a cell-based GPCR screening will identify partaking neurons. Zinc finger nuclease-mediated knockout of circuit-specific transcription factors as identified from the Atlas will reveal circuit-specific gene regulatory networks, downstream effector genes and functional characteristics. Laser ablation of GFP-labeled single neurons and axonal connections will yield further insight into the function of circuit components and subcircuits. Given the ancient nature of the Platynereis brain, this research is expected to reveal a simple, developmental and evolutionary “blueprint” for the olfactory circuits in mice and flies and to shed new light on the evolution of information processing in glomeruli and higher-level integration in sensory-associative brain centres.
Summary
Neural circuits, composed of interconnected neurons, represent the basic unit of the nervous system. One way to understand the highly complex arrangement of cross-talking, serial and parallel circuits is to resolve its developmental and evolutionary emergence. The rationale of the research proposal presented here is to elucidate the complex circuitry of the vertebrate and insect forebrain by comparison to the much simpler and evolutionary ancient “connectome” of the marine annelid Platynereis dumerilii. We will build a unique resource, the Platynereis Neuron Type Atlas, combining, for the first time, neuronal morphologies, axonal projections, cellular expression profiling and developmental lineage for an entire bilaterian brain. We will focus on five days old larvae when most adult neuron types are already present in small number and large part of the axonal scaffold in place.
Building on the Neuron Type Atlas, the second part of the proposal envisages the functional dissection of the Platynereis chemosensory-motor forebrain circuits. A newly developed microfluidics behavioural assay system, together with a cell-based GPCR screening will identify partaking neurons. Zinc finger nuclease-mediated knockout of circuit-specific transcription factors as identified from the Atlas will reveal circuit-specific gene regulatory networks, downstream effector genes and functional characteristics. Laser ablation of GFP-labeled single neurons and axonal connections will yield further insight into the function of circuit components and subcircuits. Given the ancient nature of the Platynereis brain, this research is expected to reveal a simple, developmental and evolutionary “blueprint” for the olfactory circuits in mice and flies and to shed new light on the evolution of information processing in glomeruli and higher-level integration in sensory-associative brain centres.
Max ERC Funding
2 489 048 €
Duration
Start date: 2012-03-01, End date: 2017-02-28
Project acronym BRAINGAIN
Project NOVEL STRATEGIES FOR BRAIN REGENERATION
Researcher (PI) Andras Simon
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS3, ERC-2011-StG_20101109
Summary In contrast to mammals, newts possess exceptional capacities among vertebrates to rebuild complex structures, such as the brain. Our goal is to bridge the gap in the regenerative outcomes between newts and mammals. My group has made significant contributions towards this goal. We created a novel experimental system, which recapitulates central features of Parkinson’s disease in newts, and provides a unique model for understanding regeneration in the adult midbrain. We showed an unexpected but key feature of the newt brain that it is akin to the mammalian brain in terms of the extent of homeostatic cell turn over, but distinct in terms of its injury response, showing the regenerative capacity of the adult vertebrate brain by activating neurogenesis in normally quiescent regions. Further we established a critical role for the neurotransmitter dopamine in controlling quiescence in the midbrain, thereby preventing neurogenesis during homeostasis and terminating neurogenesis once the correct number of neurons has been produced during regeneration. Here we aim to identify key molecular pathways that regulate adult neurogenesis, to define lineage relationships between neuronal stem and progenitor cells, and to identify essential differences between newts and mammals. We will combine pharmacological modulation of neurotransmitter signaling with extensive cellular fate mapping approaches, and molecular manipulations. Ultimately we will test hypotheses derived from newt studies with mammalian systems including newt/mouse cross species complementation approaches. We expect that our findings will provide new regenerative strategies, and reveal fundamental aspects of cell fate determination, tissue growth, and tissue maintenance in normal and pathological conditions.
Summary
In contrast to mammals, newts possess exceptional capacities among vertebrates to rebuild complex structures, such as the brain. Our goal is to bridge the gap in the regenerative outcomes between newts and mammals. My group has made significant contributions towards this goal. We created a novel experimental system, which recapitulates central features of Parkinson’s disease in newts, and provides a unique model for understanding regeneration in the adult midbrain. We showed an unexpected but key feature of the newt brain that it is akin to the mammalian brain in terms of the extent of homeostatic cell turn over, but distinct in terms of its injury response, showing the regenerative capacity of the adult vertebrate brain by activating neurogenesis in normally quiescent regions. Further we established a critical role for the neurotransmitter dopamine in controlling quiescence in the midbrain, thereby preventing neurogenesis during homeostasis and terminating neurogenesis once the correct number of neurons has been produced during regeneration. Here we aim to identify key molecular pathways that regulate adult neurogenesis, to define lineage relationships between neuronal stem and progenitor cells, and to identify essential differences between newts and mammals. We will combine pharmacological modulation of neurotransmitter signaling with extensive cellular fate mapping approaches, and molecular manipulations. Ultimately we will test hypotheses derived from newt studies with mammalian systems including newt/mouse cross species complementation approaches. We expect that our findings will provide new regenerative strategies, and reveal fundamental aspects of cell fate determination, tissue growth, and tissue maintenance in normal and pathological conditions.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-02-01, End date: 2017-01-31
Project acronym CELLCONTROL
Project Synthetic regulatory circuits for programmable control of cell physiology
Researcher (PI) Yaakov Benenson
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Starting Grant (StG), LS9, ERC-2011-StG_20101109
Summary The newly emerging discipline of Synthetic Biology holds the promise of radically changing the way we probe, control and augment living matter from single cells to entire organisms, and revolutionize basic biological research, biotechnology, and medicine. However, practical work toward these important goals is still in its infancy, in part because concrete approaches to achieve rational control of cell physiology are currently lacking. In order to advance this vision, here we propose a detailed strategy toward engineered regulatory circuits that read out complex cellular states based on multiple biological signals, and convert this information into a desired action based on pre-programmed signal integration. If successful, our strategy will enable unprecedented level of rational intervention with the cell.
Specifically, we suggest to read out cellular information as relayed by expression and activity of cell’s transcription factors, proteins that control gene expression and serve as major regulators of cell fate and cell response to transient stimuli. The readout will be accomplished with the help of specially-designed sensor promoters that will in turn drive the expression of engineered microRNA molecules. Those molecules in turn will converge on a small number of response elements in engineered downstream transcripts, implementing highly-flexible and programmable logic integration of the original transcription factor signals (Rinaudo et al, Nature Biotechnology, 2007 and Leisner et al, Nature Nanotechnology, 2010).
We propose a stepwise bottom-up construction strategy whereby we first design, test and optimize sensor promoters for individual TFs, next we integrate them into large networks, and finally we show how to utilize these networks as prototype selective anti-cancer therapies. To validate our approaches, we will use human cancer cell lines as a model system.
Summary
The newly emerging discipline of Synthetic Biology holds the promise of radically changing the way we probe, control and augment living matter from single cells to entire organisms, and revolutionize basic biological research, biotechnology, and medicine. However, practical work toward these important goals is still in its infancy, in part because concrete approaches to achieve rational control of cell physiology are currently lacking. In order to advance this vision, here we propose a detailed strategy toward engineered regulatory circuits that read out complex cellular states based on multiple biological signals, and convert this information into a desired action based on pre-programmed signal integration. If successful, our strategy will enable unprecedented level of rational intervention with the cell.
Specifically, we suggest to read out cellular information as relayed by expression and activity of cell’s transcription factors, proteins that control gene expression and serve as major regulators of cell fate and cell response to transient stimuli. The readout will be accomplished with the help of specially-designed sensor promoters that will in turn drive the expression of engineered microRNA molecules. Those molecules in turn will converge on a small number of response elements in engineered downstream transcripts, implementing highly-flexible and programmable logic integration of the original transcription factor signals (Rinaudo et al, Nature Biotechnology, 2007 and Leisner et al, Nature Nanotechnology, 2010).
We propose a stepwise bottom-up construction strategy whereby we first design, test and optimize sensor promoters for individual TFs, next we integrate them into large networks, and finally we show how to utilize these networks as prototype selective anti-cancer therapies. To validate our approaches, we will use human cancer cell lines as a model system.
Max ERC Funding
1 479 009 €
Duration
Start date: 2011-10-01, End date: 2017-09-30
Project acronym CELLPATTERN
Project The Cellular Basis of Multicellular Pattern Formation
Researcher (PI) Dolf Weijers
Host Institution (HI) WAGENINGEN UNIVERSITY
Call Details Starting Grant (StG), LS3, ERC-2011-StG_20101109
Summary The formation of plant organs (leaves, roots, flowers) depends on the activity of stem cells (SC), located in stem cell niches (meristems) together with adjoining organizer cells (OC) that prevent SC differentiation. Despite their importance, SC and OC have been poorly described at molecular and cellular level and mechanisms for their coordinated specification are only partially understood. We study the specification of the very first SC and OC for the root in the early Arabidopsis embryo where cell divisions are almost invariant and, in the absence of cell motility, highly predictable. Previously we have established a central role for the transcription factor MONOPTEROS (MP) in OC specification and we have recently found that MP also controls SC specification. Hence, MP offers a unique entry point into studying the genomic and cellular reprogramming that underlies coordinated SC and OC specification. Our recent identification of MP target genes has shown that its function in SC specification is cell-autonomous, while MP-dependent OC specification involves a mobile transcription factor.
In recent years we have developed a set of resources to systematically study embryonic root meristem initiation, and are now in a unique position to answer the following questions in this ERC project:
1. What transcriptional reprogramming underlies the first specification of SC and OC in the plant embryo?
2. What cellular changes follow from transcriptional reprogramming and mediate elongation and asymmetric division of SC and OC?
3. What is the mechanism of directional protein transport that ensures spatiotemporal coordination between SC and OC?
The project will provide genome-wide insight in the cellular reprogramming underlying the coordinated formation of a multicellular structure. Finally, this work will shed light on mechanisms of stem cell and stem cell niche formation.
Summary
The formation of plant organs (leaves, roots, flowers) depends on the activity of stem cells (SC), located in stem cell niches (meristems) together with adjoining organizer cells (OC) that prevent SC differentiation. Despite their importance, SC and OC have been poorly described at molecular and cellular level and mechanisms for their coordinated specification are only partially understood. We study the specification of the very first SC and OC for the root in the early Arabidopsis embryo where cell divisions are almost invariant and, in the absence of cell motility, highly predictable. Previously we have established a central role for the transcription factor MONOPTEROS (MP) in OC specification and we have recently found that MP also controls SC specification. Hence, MP offers a unique entry point into studying the genomic and cellular reprogramming that underlies coordinated SC and OC specification. Our recent identification of MP target genes has shown that its function in SC specification is cell-autonomous, while MP-dependent OC specification involves a mobile transcription factor.
In recent years we have developed a set of resources to systematically study embryonic root meristem initiation, and are now in a unique position to answer the following questions in this ERC project:
1. What transcriptional reprogramming underlies the first specification of SC and OC in the plant embryo?
2. What cellular changes follow from transcriptional reprogramming and mediate elongation and asymmetric division of SC and OC?
3. What is the mechanism of directional protein transport that ensures spatiotemporal coordination between SC and OC?
The project will provide genome-wide insight in the cellular reprogramming underlying the coordinated formation of a multicellular structure. Finally, this work will shed light on mechanisms of stem cell and stem cell niche formation.
Max ERC Funding
1 499 070 €
Duration
Start date: 2011-10-01, End date: 2016-09-30
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