Project acronym 3DBIOLUNG
Project Bioengineering lung tissue using extracellular matrix based 3D bioprinting
Researcher (PI) Darcy WAGNER
Host Institution (HI) LUNDS UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), LS9, ERC-2018-STG
Summary Chronic lung diseases are increasing in prevalence with over 65 million patients worldwide. Lung transplantation remains the only potential option at end-stage disease. Around 4000 patients receive lung transplants annually with more awaiting transplantation, including 1000 patients in Europe. New options to increase available tissue for lung transplantation are desperately needed.
An exciting new research area focuses on generating lung tissue ex vivo using bioengineering approaches. Scaffolds can be generated from synthetic or biologically-derived (acellular) materials, seeded with cells and grown in a bioreactor prior to transplantation. Ideally, scaffolds would be seeded with cells derived from the transplant recipient, thus obviating the need for long-term immunosuppression. However, functional regeneration has yet to be achieved. New advances in 3D printing and 3D bioprinting (when cells are printed) indicate that this once thought of science-fiction concept might finally be mature enough for complex tissues, including lung. 3D bioprinting addresses a number of concerns identified in previous approaches, such as a) patient heterogeneity in acellular human scaffolds, b) anatomical differences in xenogeneic sources, c) lack of biological cues on synthetic materials and d) difficulty in manufacturing the complex lung architecture. 3D bioprinting could be a reproducible, scalable, and controllable approach for generating functional lung tissue.
The aim of this proposal is to use custom 3D bioprinters to generate constructs mimicking lung tissue using an innovative approach combining primary cells, the engineering reproducibility of synthetic materials, and the biologically conductive properties of acellular lung (hybrid). We will 3D bioprint hybrid murine and human lung tissue models and test gas exchange, angiogenesis and in vivo immune responses. This proposal will be a critical first step in demonstrating feasibility of 3D bioprinting lung tissue.
Summary
Chronic lung diseases are increasing in prevalence with over 65 million patients worldwide. Lung transplantation remains the only potential option at end-stage disease. Around 4000 patients receive lung transplants annually with more awaiting transplantation, including 1000 patients in Europe. New options to increase available tissue for lung transplantation are desperately needed.
An exciting new research area focuses on generating lung tissue ex vivo using bioengineering approaches. Scaffolds can be generated from synthetic or biologically-derived (acellular) materials, seeded with cells and grown in a bioreactor prior to transplantation. Ideally, scaffolds would be seeded with cells derived from the transplant recipient, thus obviating the need for long-term immunosuppression. However, functional regeneration has yet to be achieved. New advances in 3D printing and 3D bioprinting (when cells are printed) indicate that this once thought of science-fiction concept might finally be mature enough for complex tissues, including lung. 3D bioprinting addresses a number of concerns identified in previous approaches, such as a) patient heterogeneity in acellular human scaffolds, b) anatomical differences in xenogeneic sources, c) lack of biological cues on synthetic materials and d) difficulty in manufacturing the complex lung architecture. 3D bioprinting could be a reproducible, scalable, and controllable approach for generating functional lung tissue.
The aim of this proposal is to use custom 3D bioprinters to generate constructs mimicking lung tissue using an innovative approach combining primary cells, the engineering reproducibility of synthetic materials, and the biologically conductive properties of acellular lung (hybrid). We will 3D bioprint hybrid murine and human lung tissue models and test gas exchange, angiogenesis and in vivo immune responses. This proposal will be a critical first step in demonstrating feasibility of 3D bioprinting lung tissue.
Max ERC Funding
1 499 975 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym 3DPROTEINPUZZLES
Project Shape-directed protein assembly design
Researcher (PI) Lars Ingemar ANDRe
Host Institution (HI) MAX IV Laboratory, Lund University
Country Sweden
Call Details Consolidator Grant (CoG), LS9, ERC-2017-COG
Summary Large protein complexes carry out some of the most complex functions in biology. Such structures are often assembled spontaneously from individual components through the process of self-assembly. If self-assembled protein complexes could be engineered from first principle it would enable a wide range of applications in biomedicine, nanotechnology and materials science. Recently, approaches to rationally design proteins to self-assembly into predefined structures have emerged. The highlight of this work is the design of protein cages that may be engineered into protein containers. However, current approaches for self-assembly design does not result in the assemblies with the required structural complexity to encode many of the sophisticated functions found in nature. To move forward, we have to learn how to engineer protein subunits with more than one designed interface that can assemble into tightly interacting complexes. In this proposal we propose a new protein design paradigm, shape directed protein design, in order to address shortcomings of the current methodology. The proposed method combines geometric shape matching and computational protein design. Using this approach we will de novo design assemblies with a wide variety of structural states, including protein complexes with cyclic and dihedral symmetry as well as icosahedral protein capsids built from novel protein building blocks. To enable these two design challenges we also develop a high-throughput assay to measure assembly stability in vivo that builds on a three-color fluorescent assay. This method will not only facilitate the screening of orders of magnitude more design constructs, but also enable the application of directed evolution to experimentally improve stable and assembly properties of designed containers as well as other designed assemblies.
Summary
Large protein complexes carry out some of the most complex functions in biology. Such structures are often assembled spontaneously from individual components through the process of self-assembly. If self-assembled protein complexes could be engineered from first principle it would enable a wide range of applications in biomedicine, nanotechnology and materials science. Recently, approaches to rationally design proteins to self-assembly into predefined structures have emerged. The highlight of this work is the design of protein cages that may be engineered into protein containers. However, current approaches for self-assembly design does not result in the assemblies with the required structural complexity to encode many of the sophisticated functions found in nature. To move forward, we have to learn how to engineer protein subunits with more than one designed interface that can assemble into tightly interacting complexes. In this proposal we propose a new protein design paradigm, shape directed protein design, in order to address shortcomings of the current methodology. The proposed method combines geometric shape matching and computational protein design. Using this approach we will de novo design assemblies with a wide variety of structural states, including protein complexes with cyclic and dihedral symmetry as well as icosahedral protein capsids built from novel protein building blocks. To enable these two design challenges we also develop a high-throughput assay to measure assembly stability in vivo that builds on a three-color fluorescent assay. This method will not only facilitate the screening of orders of magnitude more design constructs, but also enable the application of directed evolution to experimentally improve stable and assembly properties of designed containers as well as other designed assemblies.
Max ERC Funding
2 325 292 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym 4C
Project 4C technology: uncovering the multi-dimensional structure of the genome
Researcher (PI) Wouter Leonard De Laat
Host Institution (HI) KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Country Netherlands
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary The architecture of DNA in the cell nucleus is an emerging epigenetic key contributor to genome function. We recently developed 4C technology, a high-throughput technique that combines state-of-the-art 3C technology with tailored micro-arrays to uniquely allow for an unbiased genome-wide search for DNA loci that interact in the nuclear space. Based on 4C technology, we were the first to provide a comprehensive overview of long-range DNA contacts of selected loci. The data showed that active and inactive chromatin domains contact many distinct regions within and between chromosomes and genes switch long-range DNA contacts in relation to their expression status. 4C technology not only allows investigating the three-dimensional structure of DNA in the nucleus, it also accurately reconstructs at least 10 megabases of the one-dimensional chromosome sequence map around the target sequence. Changes in this physical map as a result of genomic rearrangements are therefore identified by 4C technology. We recently demonstrated that 4C detects deletions, balanced inversions and translocations in patient samples at a resolution (~7kb) that allowed immediate sequencing of the breakpoints. Excitingly, 4C technology therefore offers the first high-resolution genomic approach that can identify both balanced and unbalanced genomic rearrangements. 4C is expected to become an important tool in clinical diagnosis and prognosis. Key objectives of this proposal are: 1. Explore the functional significance of DNA folding in the nucleus by systematically applying 4C technology to differentially expressed gene loci. 2. Adapt 4C technology such that it allows for massive parallel analysis of DNA interactions between regulatory elements and gene promoters. This method would greatly facilitate the identification of functionally relevant DNA elements in the genome. 3. Develop 4C technology into a clinical diagnostic tool for the accurate detection of balanced and unbalanced rearrangements.
Summary
The architecture of DNA in the cell nucleus is an emerging epigenetic key contributor to genome function. We recently developed 4C technology, a high-throughput technique that combines state-of-the-art 3C technology with tailored micro-arrays to uniquely allow for an unbiased genome-wide search for DNA loci that interact in the nuclear space. Based on 4C technology, we were the first to provide a comprehensive overview of long-range DNA contacts of selected loci. The data showed that active and inactive chromatin domains contact many distinct regions within and between chromosomes and genes switch long-range DNA contacts in relation to their expression status. 4C technology not only allows investigating the three-dimensional structure of DNA in the nucleus, it also accurately reconstructs at least 10 megabases of the one-dimensional chromosome sequence map around the target sequence. Changes in this physical map as a result of genomic rearrangements are therefore identified by 4C technology. We recently demonstrated that 4C detects deletions, balanced inversions and translocations in patient samples at a resolution (~7kb) that allowed immediate sequencing of the breakpoints. Excitingly, 4C technology therefore offers the first high-resolution genomic approach that can identify both balanced and unbalanced genomic rearrangements. 4C is expected to become an important tool in clinical diagnosis and prognosis. Key objectives of this proposal are: 1. Explore the functional significance of DNA folding in the nucleus by systematically applying 4C technology to differentially expressed gene loci. 2. Adapt 4C technology such that it allows for massive parallel analysis of DNA interactions between regulatory elements and gene promoters. This method would greatly facilitate the identification of functionally relevant DNA elements in the genome. 3. Develop 4C technology into a clinical diagnostic tool for the accurate detection of balanced and unbalanced rearrangements.
Max ERC Funding
1 225 000 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
Project acronym ABCTRANSPORT
Project Minimalist multipurpose ATP-binding cassette transporters
Researcher (PI) Dirk Jan Slotboom
Host Institution (HI) RIJKSUNIVERSITEIT GRONINGEN
Country Netherlands
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary Many Gram-positive (pathogenic) bacteria are dependent on the uptake of vitamins from the environment or from the infected host. We have recently discovered the long-elusive family of membrane protein complexes catalyzing such transport. The vitamin transporters have an unprecedented modular architecture consisting of a single multipurpose energizing module (the Energy Coupling Factor, ECF) and multiple exchangeable membrane proteins responsible for substrate recognition (S-components). The S-components have characteristics of ion-gradient driven transporters (secondary active transporters), whereas the energizing modules are related to ATP-binding cassette (ABC) transporters (primary active transporters).
The aim of the proposal is threefold: First, we will address the question how properties of primary and secondary transporters are combined in ECF transporters to obtain a novel transport mechanism. Second, we will study the fundamental and unresolved question how protein-protein recognition takes place in the hydrophobic environment of the lipid bilayer. The modular nature of the ECF proteins offers a natural system to study the driving forces used for membrane protein interaction. Third, we will assess whether the ECF transport systems could become targets for antibacterial drugs. ECF transporters are found exclusively in prokaryotes, and their activity is often essential for viability of Gram-positive pathogens. Thus they could turn out to be an Achilles’ heel for the organisms.
Structural and mechanistic studies (X-ray crystallography, microscopy, spectroscopy and biochemistry) will reveal how the different transport modes are combined in a single protein complex, how transport is energized and catalyzed, and how protein-protein recognition takes place. Microbiological screens will be developed to search for compounds that inhibit prokaryote-specific steps of the mechanism of ECF transporters.
Summary
Many Gram-positive (pathogenic) bacteria are dependent on the uptake of vitamins from the environment or from the infected host. We have recently discovered the long-elusive family of membrane protein complexes catalyzing such transport. The vitamin transporters have an unprecedented modular architecture consisting of a single multipurpose energizing module (the Energy Coupling Factor, ECF) and multiple exchangeable membrane proteins responsible for substrate recognition (S-components). The S-components have characteristics of ion-gradient driven transporters (secondary active transporters), whereas the energizing modules are related to ATP-binding cassette (ABC) transporters (primary active transporters).
The aim of the proposal is threefold: First, we will address the question how properties of primary and secondary transporters are combined in ECF transporters to obtain a novel transport mechanism. Second, we will study the fundamental and unresolved question how protein-protein recognition takes place in the hydrophobic environment of the lipid bilayer. The modular nature of the ECF proteins offers a natural system to study the driving forces used for membrane protein interaction. Third, we will assess whether the ECF transport systems could become targets for antibacterial drugs. ECF transporters are found exclusively in prokaryotes, and their activity is often essential for viability of Gram-positive pathogens. Thus they could turn out to be an Achilles’ heel for the organisms.
Structural and mechanistic studies (X-ray crystallography, microscopy, spectroscopy and biochemistry) will reveal how the different transport modes are combined in a single protein complex, how transport is energized and catalyzed, and how protein-protein recognition takes place. Microbiological screens will be developed to search for compounds that inhibit prokaryote-specific steps of the mechanism of ECF transporters.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-01-01, End date: 2017-12-31
Project acronym ABCvolume
Project The ABC of Cell Volume Regulation
Researcher (PI) Berend Poolman
Host Institution (HI) RIJKSUNIVERSITEIT GRONINGEN
Country Netherlands
Call Details Advanced Grant (AdG), LS1, ERC-2014-ADG
Summary Cell volume regulation is crucial for any living cell because changes in volume determine the metabolic activity through e.g. changes in ionic strength, pH, macromolecular crowding and membrane tension. These physical chemical parameters influence interaction rates and affinities of biomolecules, folding rates, and fold stabilities in vivo. Understanding of the underlying volume regulatory mechanisms has immediate application in biotechnology and health, yet these factors are generally ignored in systems analyses of cellular functions.
My team has uncovered a number of mechanisms and insights of cell volume regulation. The next step forward is to elucidate how the components of a cell volume regulatory circuit work together and control the physicochemical conditions of the cell.
I propose construction of a synthetic cell in which an osmoregulatory transporter and mechanosensitive channel form a minimal volume regulatory network. My group has developed the technology to reconstitute membrane proteins into lipid vesicles (synthetic cells). One of the challenges is to incorporate into the vesicles an efficient pathway for ATP production and maintain energy homeostasis while the load on the system varies. We aim to control the transmembrane flux of osmolytes, which requires elucidation of the molecular mechanism of gating of the osmoregulatory transporter. We will focus on the glycine betaine ABC importer, which is one of the most complex transporters known to date with ten distinct protein domains, transiently interacting with each other.
The proposed synthetic metabolic circuit constitutes a fascinating out-of-equilibrium system, allowing us to understand cell volume regulatory mechanisms in a context and at a level of complexity minimally needed for life. Analysis of this circuit will address many outstanding questions and eventually allow us to design more sophisticated vesicular systems with applications, for example as compartmentalized reaction networks.
Summary
Cell volume regulation is crucial for any living cell because changes in volume determine the metabolic activity through e.g. changes in ionic strength, pH, macromolecular crowding and membrane tension. These physical chemical parameters influence interaction rates and affinities of biomolecules, folding rates, and fold stabilities in vivo. Understanding of the underlying volume regulatory mechanisms has immediate application in biotechnology and health, yet these factors are generally ignored in systems analyses of cellular functions.
My team has uncovered a number of mechanisms and insights of cell volume regulation. The next step forward is to elucidate how the components of a cell volume regulatory circuit work together and control the physicochemical conditions of the cell.
I propose construction of a synthetic cell in which an osmoregulatory transporter and mechanosensitive channel form a minimal volume regulatory network. My group has developed the technology to reconstitute membrane proteins into lipid vesicles (synthetic cells). One of the challenges is to incorporate into the vesicles an efficient pathway for ATP production and maintain energy homeostasis while the load on the system varies. We aim to control the transmembrane flux of osmolytes, which requires elucidation of the molecular mechanism of gating of the osmoregulatory transporter. We will focus on the glycine betaine ABC importer, which is one of the most complex transporters known to date with ten distinct protein domains, transiently interacting with each other.
The proposed synthetic metabolic circuit constitutes a fascinating out-of-equilibrium system, allowing us to understand cell volume regulatory mechanisms in a context and at a level of complexity minimally needed for life. Analysis of this circuit will address many outstanding questions and eventually allow us to design more sophisticated vesicular systems with applications, for example as compartmentalized reaction networks.
Max ERC Funding
2 247 231 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym ACTIVATION OF XCI
Project Molecular mechanisms controlling X chromosome inactivation
Researcher (PI) Joost Henk Gribnau
Host Institution (HI) ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Country Netherlands
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary In mammals, gene dosage of X-chromosomal genes is equalized between sexes by random inactivation of either one of the two X chromosomes in female cells. In the initial phase of X chromosome inactivation (XCI), a counting and initiation process determines the number of X chromosomes per nucleus, and elects the future inactive X chromosome (Xi). Xist is an X-encoded gene that plays a crucial role in the XCI process. At the start of XCI Xist expression is up-regulated and Xist RNA accumulates on the future Xi thereby initiating silencing in cis. Recent work performed in my laboratory indicates that the counting and initiation process is directed by a stochastic mechanism, in which each X chromosome has an independent probability to be inactivated. We also found that this probability is determined by the X:ploïdy ratio. These results indicated the presence of at least one X-linked activator of XCI. With a BAC screen we recently identified X-encoded RNF12 to be a dose-dependent activator of XCI. Expression of RNF12 correlates with Xist expression, and a heterozygous deletion of Rnf12 results in a marked loss of XCI in female cells. The presence of a small proportion of cells that still initiate XCI, in Rnf12+/- cells, also indicated that more XCI-activators are involved in XCI. Here, we propose to investigate the molecular mechanism by which RNF12 activates XCI in mouse and human, and to search for additional XCI-activators. We will also attempt to establish the role of different inhibitors of XCI, including CTCF and the pluripotency factors OCT4, SOX2 and NANOG. We anticipate that these studies will significantly advance our understanding of XCI mechanisms, which is highly relevant for a better insight in the manifestation of X-linked diseases that are affected by XCI.
Summary
In mammals, gene dosage of X-chromosomal genes is equalized between sexes by random inactivation of either one of the two X chromosomes in female cells. In the initial phase of X chromosome inactivation (XCI), a counting and initiation process determines the number of X chromosomes per nucleus, and elects the future inactive X chromosome (Xi). Xist is an X-encoded gene that plays a crucial role in the XCI process. At the start of XCI Xist expression is up-regulated and Xist RNA accumulates on the future Xi thereby initiating silencing in cis. Recent work performed in my laboratory indicates that the counting and initiation process is directed by a stochastic mechanism, in which each X chromosome has an independent probability to be inactivated. We also found that this probability is determined by the X:ploïdy ratio. These results indicated the presence of at least one X-linked activator of XCI. With a BAC screen we recently identified X-encoded RNF12 to be a dose-dependent activator of XCI. Expression of RNF12 correlates with Xist expression, and a heterozygous deletion of Rnf12 results in a marked loss of XCI in female cells. The presence of a small proportion of cells that still initiate XCI, in Rnf12+/- cells, also indicated that more XCI-activators are involved in XCI. Here, we propose to investigate the molecular mechanism by which RNF12 activates XCI in mouse and human, and to search for additional XCI-activators. We will also attempt to establish the role of different inhibitors of XCI, including CTCF and the pluripotency factors OCT4, SOX2 and NANOG. We anticipate that these studies will significantly advance our understanding of XCI mechanisms, which is highly relevant for a better insight in the manifestation of X-linked diseases that are affected by XCI.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym ACUITY
Project Algorithms for coping with uncertainty and intractability
Researcher (PI) Nikhil Bansal
Host Institution (HI) TECHNISCHE UNIVERSITEIT EINDHOVEN
Country Netherlands
Call Details Consolidator Grant (CoG), PE6, ERC-2013-CoG
Summary The two biggest challenges in solving practical optimization problems are computational intractability, and the presence
of uncertainty: most problems are either NP-hard, or have incomplete input data which
makes an exact computation impossible.
Recently, there has been a huge progress in our understanding of intractability, based on spectacular algorithmic and lower bound techniques. For several problems, especially those with only local constraints, we can design optimum
approximation algorithms that are provably the best possible.
However, typical optimization problems usually involve complex global constraints and are much less understood. The situation is even worse for coping with uncertainty. Most of the algorithms are based on ad-hoc techniques and there is no deeper understanding of what makes various problems easy or hard.
This proposal describes several new directions, together with concrete intermediate goals, that will break important new ground in the theory of approximation and online algorithms. The particular directions we consider are (i) extend the primal dual method to systematically design online algorithms, (ii) build a structural theory of online problems based on work functions, (iii) develop new tools to use the power of strong convex relaxations and (iv) design new algorithmic approaches based on non-constructive proof techniques.
The proposed research is at the
cutting edge of algorithm design, and builds upon the recent success of the PI in resolving several longstanding questions in these areas. Any progress is likely to be a significant contribution to theoretical
computer science and combinatorial optimization.
Summary
The two biggest challenges in solving practical optimization problems are computational intractability, and the presence
of uncertainty: most problems are either NP-hard, or have incomplete input data which
makes an exact computation impossible.
Recently, there has been a huge progress in our understanding of intractability, based on spectacular algorithmic and lower bound techniques. For several problems, especially those with only local constraints, we can design optimum
approximation algorithms that are provably the best possible.
However, typical optimization problems usually involve complex global constraints and are much less understood. The situation is even worse for coping with uncertainty. Most of the algorithms are based on ad-hoc techniques and there is no deeper understanding of what makes various problems easy or hard.
This proposal describes several new directions, together with concrete intermediate goals, that will break important new ground in the theory of approximation and online algorithms. The particular directions we consider are (i) extend the primal dual method to systematically design online algorithms, (ii) build a structural theory of online problems based on work functions, (iii) develop new tools to use the power of strong convex relaxations and (iv) design new algorithmic approaches based on non-constructive proof techniques.
The proposed research is at the
cutting edge of algorithm design, and builds upon the recent success of the PI in resolving several longstanding questions in these areas. Any progress is likely to be a significant contribution to theoretical
computer science and combinatorial optimization.
Max ERC Funding
1 519 285 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym AdaptiveResponse
Project The evolution of adaptive response mechanisms
Researcher (PI) Franz WEISSING
Host Institution (HI) RIJKSUNIVERSITEIT GRONINGEN
Country Netherlands
Call Details Advanced Grant (AdG), LS8, ERC-2017-ADG
Summary In an era of rapid climate change there is a pressing need to understand whether and how organisms are able to adapt to novel environments. Such understanding is hampered by a major divide in the life sciences. Disciplines like systems biology or neurobiology make rapid progress in unravelling the mechanisms underlying the responses of organisms to their environment, but this knowledge is insufficiently integrated in eco-evolutionary theory. Current eco-evolutionary models focus on the response patterns themselves, largely neglecting the structures and mechanisms producing these patterns. Here I propose a new, mechanism-oriented framework that views the architecture of adaptation, rather than the resulting responses, as the primary target of natural selection. I am convinced that this change in perspective will yield fundamentally new insights, necessitating the re-evaluation of many seemingly well-established eco-evolutionary principles.
My aim is to develop a comprehensive theory of the eco-evolutionary causes and consequences of the architecture underlying adaptive responses. In three parallel lines of investigation, I will study how architecture is shaped by selection, how evolved response strategies reflect the underlying architecture, and how these responses affect the eco-evolutionary dynamics and the capacity to adapt to novel conditions. All three lines have the potential of making ground-breaking contributions to eco-evolutionary theory, including: the specification of evolutionary tipping points; resolving the puzzle that real organisms evolve much faster than predicted by current theory; a new and general explanation for the evolutionary emergence of individual variation; and a framework for studying the evolution of learning and other general-purpose mechanisms. By making use of concepts from information theory and artificial intelligence, the project will also introduce various methodological innovations.
Summary
In an era of rapid climate change there is a pressing need to understand whether and how organisms are able to adapt to novel environments. Such understanding is hampered by a major divide in the life sciences. Disciplines like systems biology or neurobiology make rapid progress in unravelling the mechanisms underlying the responses of organisms to their environment, but this knowledge is insufficiently integrated in eco-evolutionary theory. Current eco-evolutionary models focus on the response patterns themselves, largely neglecting the structures and mechanisms producing these patterns. Here I propose a new, mechanism-oriented framework that views the architecture of adaptation, rather than the resulting responses, as the primary target of natural selection. I am convinced that this change in perspective will yield fundamentally new insights, necessitating the re-evaluation of many seemingly well-established eco-evolutionary principles.
My aim is to develop a comprehensive theory of the eco-evolutionary causes and consequences of the architecture underlying adaptive responses. In three parallel lines of investigation, I will study how architecture is shaped by selection, how evolved response strategies reflect the underlying architecture, and how these responses affect the eco-evolutionary dynamics and the capacity to adapt to novel conditions. All three lines have the potential of making ground-breaking contributions to eco-evolutionary theory, including: the specification of evolutionary tipping points; resolving the puzzle that real organisms evolve much faster than predicted by current theory; a new and general explanation for the evolutionary emergence of individual variation; and a framework for studying the evolution of learning and other general-purpose mechanisms. By making use of concepts from information theory and artificial intelligence, the project will also introduce various methodological innovations.
Max ERC Funding
2 500 000 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
Project acronym ADDICTION
Project Beyond the Genetics of Addiction
Researcher (PI) Jacqueline Mignon Vink
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Country Netherlands
Call Details Starting Grant (StG), SH4, ERC-2011-StG_20101124
Summary My proposal seeks to explain the complex interplay between genetic and environmental causes of individual variation in substance use and the risk for abuse. Substance use is common. Substances like nicotine and cannabis have well-known negative health consequences, while alcohol and caffeine use may be both beneficial and detrimental, depending on quantity and frequency of use. Twin studies (including my own) demonstrated that both heritable and environmental factors play a role.
My proposal on substance use (nicotine, alcohol, cannabis and caffeine) is organized around several key objectives: 1. To unravel the complex contribution of genetic and environmental factors to substance use by using extended twin family designs; 2. To identify and confirm genes and gene networks involved in substance use by using DNA-variant data; 3. To explore gene expression patterns with RNA data in substance users versus non-users; 4. To investigate biomarkers in substance users versus non-users using blood or urine; 5. To unravel relation between substance use and health by linking twin-family data to national medical databases.
To realize these aims I will use the extensive resources of the Netherlands Twin Register (NTR); including both the longitudinal phenotype database and the biological samples. I have been involved in data collection, coordination of data collection and analyzing NTR data since 1999. With my comprehensive experience in data collection, data analyses and my knowledge in the field of behavior genetics and addiction research I will be able to successfully lead this cutting-edge project. Additional data crucial for the project will be collected by my team. Large samples will be available for this study and state-of-the art methods will be used to analyze the data. All together, my project will offer powerful approaches to unravel the complex interaction between genetic and environmental causes of individual differences in substance use and the risk for abuse.
Summary
My proposal seeks to explain the complex interplay between genetic and environmental causes of individual variation in substance use and the risk for abuse. Substance use is common. Substances like nicotine and cannabis have well-known negative health consequences, while alcohol and caffeine use may be both beneficial and detrimental, depending on quantity and frequency of use. Twin studies (including my own) demonstrated that both heritable and environmental factors play a role.
My proposal on substance use (nicotine, alcohol, cannabis and caffeine) is organized around several key objectives: 1. To unravel the complex contribution of genetic and environmental factors to substance use by using extended twin family designs; 2. To identify and confirm genes and gene networks involved in substance use by using DNA-variant data; 3. To explore gene expression patterns with RNA data in substance users versus non-users; 4. To investigate biomarkers in substance users versus non-users using blood or urine; 5. To unravel relation between substance use and health by linking twin-family data to national medical databases.
To realize these aims I will use the extensive resources of the Netherlands Twin Register (NTR); including both the longitudinal phenotype database and the biological samples. I have been involved in data collection, coordination of data collection and analyzing NTR data since 1999. With my comprehensive experience in data collection, data analyses and my knowledge in the field of behavior genetics and addiction research I will be able to successfully lead this cutting-edge project. Additional data crucial for the project will be collected by my team. Large samples will be available for this study and state-of-the art methods will be used to analyze the data. All together, my project will offer powerful approaches to unravel the complex interaction between genetic and environmental causes of individual differences in substance use and the risk for abuse.
Max ERC Funding
1 491 964 €
Duration
Start date: 2011-12-01, End date: 2017-05-31
Project acronym ADDICTIONCIRCUITS
Project Drug addiction: molecular changes in reward and aversion circuits
Researcher (PI) Nils David Engblom
Host Institution (HI) LINKOPINGS UNIVERSITET
Country Sweden
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary Our affective and motivational state is important for our decisions, actions and quality of life. Many pathological conditions affect this state. For example, addictive drugs are hyperactivating the reward system and trigger a strong motivation for continued drug intake, whereas many somatic and psychiatric diseases lead to an aversive state, characterized by loss of motivation. I will study specific neural circuits and mechanisms underlying reward and aversion, and how pathological signaling in these systems can trigger relapse in drug addiction.
Given the important role of the dopaminergic neurons in the midbrain for many aspects of reward signaling, I will study how synaptic plasticity in these cells, and in their target neurons in the striatum, contribute to relapse in drug seeking. I will also study the circuits underlying aversion. Little is known about these circuits, but my hypothesis is that an important component of aversion is signaled by a specific neuronal population in the brainstem parabrachial nucleus, projecting to the central amygdala. We will test this hypothesis and also determine how this aversion circuit contributes to the persistence of addiction and to relapse.
To dissect this complicated system, I am developing new genetic methods for manipulating and visualizing specific functional circuits in the mouse brain. My unique combination of state-of-the-art competence in transgenics and cutting edge knowledge in the anatomy and functional organization of the circuits behind reward and aversion should allow me to decode these systems, linking discrete circuits to behavior.
Collectively, the results will indicate how signals encoding aversion and reward are integrated to control addictive behavior and they may identify novel avenues for treatment of drug addiction as well as aversion-related symptoms affecting patients with chronic inflammatory conditions and cancer.
Summary
Our affective and motivational state is important for our decisions, actions and quality of life. Many pathological conditions affect this state. For example, addictive drugs are hyperactivating the reward system and trigger a strong motivation for continued drug intake, whereas many somatic and psychiatric diseases lead to an aversive state, characterized by loss of motivation. I will study specific neural circuits and mechanisms underlying reward and aversion, and how pathological signaling in these systems can trigger relapse in drug addiction.
Given the important role of the dopaminergic neurons in the midbrain for many aspects of reward signaling, I will study how synaptic plasticity in these cells, and in their target neurons in the striatum, contribute to relapse in drug seeking. I will also study the circuits underlying aversion. Little is known about these circuits, but my hypothesis is that an important component of aversion is signaled by a specific neuronal population in the brainstem parabrachial nucleus, projecting to the central amygdala. We will test this hypothesis and also determine how this aversion circuit contributes to the persistence of addiction and to relapse.
To dissect this complicated system, I am developing new genetic methods for manipulating and visualizing specific functional circuits in the mouse brain. My unique combination of state-of-the-art competence in transgenics and cutting edge knowledge in the anatomy and functional organization of the circuits behind reward and aversion should allow me to decode these systems, linking discrete circuits to behavior.
Collectively, the results will indicate how signals encoding aversion and reward are integrated to control addictive behavior and they may identify novel avenues for treatment of drug addiction as well as aversion-related symptoms affecting patients with chronic inflammatory conditions and cancer.
Max ERC Funding
1 500 000 €
Duration
Start date: 2010-10-01, End date: 2015-09-30
