Project acronym BIOUNCERTAINTY
Project Deep uncertainties in bioethics: genetic research, preventive medicine, reproductive decisions
Researcher (PI) Tomasz ZURADZKI
Host Institution (HI) UNIWERSYTET JAGIELLONSKI
Country Poland
Call Details Starting Grant (StG), SH5, ERC-2018-STG
Summary Uncertainty is everywhere, as the saying goes, but rarely considered in ethical reflections. This project aims to reinterpret ethical discussions on current advances in biomedicine: instead of understanding bioethical positions as extensions of classical normative views in ethics (consequentialism, deontologism, contractualism etc.), my project interprets them more accurately as involving various normative approaches to decision making under uncertainty. The following hard cases in bioethics provide the motivation for research:
1) Regulating scientific research under uncertainty about the ontological/moral status (e.g. parthenogenetic stem cells derived from human parthenotes) in the context of meta-reasoning under normative uncertainty.
2) The value of preventive medicine in healthcare (e.g. vaccinations) in the context of decision-making under metaphysical indeterminacy.
3) Population or reproductive decisions (e.g. preimplantation genetic diagnosis) in the context of valuing mere existence.
The main drive behind this project is the rapid progress in biomedical research combined with new kinds of uncertainties. These new and “deep” uncertainties trigger specific forms of emotions and cognitions that influence normative judgments and decisions. The main research questions that will be addressed by conceptual analysis, new psychological experiments, and case studies are the following: how do the heuristics and biases (H&B) documented by behavioral scientists influence the formation of normative judgments in bioethical contexts; how to demarcate between distorted and undistorted value judgments; to what extent is it permissible for individuals or policy makers to yield to H&B. The hypothesis is that many existing bioethical rules, regulations, practices seem to have emerged from unreliable reactions, rather than by means of deliberation on the possible justifications for alternative ways to decide about them under several layers and types of uncertainty.
Summary
Uncertainty is everywhere, as the saying goes, but rarely considered in ethical reflections. This project aims to reinterpret ethical discussions on current advances in biomedicine: instead of understanding bioethical positions as extensions of classical normative views in ethics (consequentialism, deontologism, contractualism etc.), my project interprets them more accurately as involving various normative approaches to decision making under uncertainty. The following hard cases in bioethics provide the motivation for research:
1) Regulating scientific research under uncertainty about the ontological/moral status (e.g. parthenogenetic stem cells derived from human parthenotes) in the context of meta-reasoning under normative uncertainty.
2) The value of preventive medicine in healthcare (e.g. vaccinations) in the context of decision-making under metaphysical indeterminacy.
3) Population or reproductive decisions (e.g. preimplantation genetic diagnosis) in the context of valuing mere existence.
The main drive behind this project is the rapid progress in biomedical research combined with new kinds of uncertainties. These new and “deep” uncertainties trigger specific forms of emotions and cognitions that influence normative judgments and decisions. The main research questions that will be addressed by conceptual analysis, new psychological experiments, and case studies are the following: how do the heuristics and biases (H&B) documented by behavioral scientists influence the formation of normative judgments in bioethical contexts; how to demarcate between distorted and undistorted value judgments; to what extent is it permissible for individuals or policy makers to yield to H&B. The hypothesis is that many existing bioethical rules, regulations, practices seem to have emerged from unreliable reactions, rather than by means of deliberation on the possible justifications for alternative ways to decide about them under several layers and types of uncertainty.
Max ERC Funding
1 499 625 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym CoSI
Project Functional connectomics of the amygdala in social interactions of different valence
Researcher (PI) Ewelina KNAPSKA
Host Institution (HI) INSTYTUT BIOLOGII DOSWIADCZALNEJ IM. M. NENCKIEGO POLSKIEJ AKADEMII NAUK
Country Poland
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary Understanding how brain controls social interactions is one of the central goals of neuroscience. Whereas social interactions and their effects on the emotional state of an individual are relatively well described at the behavioral level, much less is known about neural mechanisms involved in these very complex phenomena, especially in the amygdala, a key structure processing emotions in the brain.
Recent investigations, mainly on fear learning and extinction, have shown that there are highly specialized neuronal circuits within the amygdala that control specific behaviors. However, a high density of interconnections, both among amygdalar nuclei and between amygdalar nuclei and other brain regions, and the lack of a predictable distribution of functional cell types make defining behavioral functions of the amygdalar neuronal circuits challenging. Therefore, to understand how different neuronal circuits in the amygdala produce different behaviors tracing anatomical connections between activated neurons, i.e., the functional anatomy is needed.
Published data and our preliminary results suggest that within the amygdala there exist different neuronal circuits mediating social interactions of different valence (positive or negative affective significance) and that circuits controlling social and non-social emotions differ. Combining our recently developed behavioral models of adult, non-aggressive, same-sex social interactions with the methods of tracing anatomical connections between activated neurons, we plan to identify neural circuitry underlying social interactions of different emotional valence. This goal will be achieved by: (1) Characterizing functional anatomy of neuronal circuits in the amygdala underlying socially transferred emotions; (2) Examining role of the identified neuronal subpopulations in control of social behaviors; (3) Verifying role of matrix metalloproteinase-9-dependent neuronal subpopulations within the amygdala in social motivation.
Summary
Understanding how brain controls social interactions is one of the central goals of neuroscience. Whereas social interactions and their effects on the emotional state of an individual are relatively well described at the behavioral level, much less is known about neural mechanisms involved in these very complex phenomena, especially in the amygdala, a key structure processing emotions in the brain.
Recent investigations, mainly on fear learning and extinction, have shown that there are highly specialized neuronal circuits within the amygdala that control specific behaviors. However, a high density of interconnections, both among amygdalar nuclei and between amygdalar nuclei and other brain regions, and the lack of a predictable distribution of functional cell types make defining behavioral functions of the amygdalar neuronal circuits challenging. Therefore, to understand how different neuronal circuits in the amygdala produce different behaviors tracing anatomical connections between activated neurons, i.e., the functional anatomy is needed.
Published data and our preliminary results suggest that within the amygdala there exist different neuronal circuits mediating social interactions of different valence (positive or negative affective significance) and that circuits controlling social and non-social emotions differ. Combining our recently developed behavioral models of adult, non-aggressive, same-sex social interactions with the methods of tracing anatomical connections between activated neurons, we plan to identify neural circuitry underlying social interactions of different emotional valence. This goal will be achieved by: (1) Characterizing functional anatomy of neuronal circuits in the amygdala underlying socially transferred emotions; (2) Examining role of the identified neuronal subpopulations in control of social behaviors; (3) Verifying role of matrix metalloproteinase-9-dependent neuronal subpopulations within the amygdala in social motivation.
Max ERC Funding
1 312 500 €
Duration
Start date: 2016-12-01, End date: 2021-11-30
Project acronym CULTURECONTACT
Project Europe and America in contact: a multidisciplinary study of cross-cultural transfer in the New World across time
Researcher (PI) Justyna Agnieszka Olko
Host Institution (HI) UNIWERSYTET WARSZAWSKI
Country Poland
Call Details Starting Grant (StG), SH6, ERC-2012-StG_20111124
Summary "At the core of this research proposal is the aim of reconstructing and understanding the nature, exact trajectories, mechanisms and implications of cross-cultural contact and transfers between Europeans and the native people of the Americas, focusing on, but not limited to, the Nahuatl-speaking zone of central Mexico. A major innovation of this project is to study this process of cross-cultural communication in its full historical depth, through the colonial and postcolonial eras up to the present day and encompassing different stages and types of contact. The meticulous and cross-disciplinary study of an extensive body of texts in Nahuatl (“Aztec”) and Spanish, complemented by present-day ethnolinguistic data, will make it possible to deduce and understand patterns across time and space in ways novel to existing scholarship, embracing both micro- and macroregional trends. The proposed research starts with identifying transfers in language, studied systematically through the creation of extensive databases, but leads to exploring the substance of cross-cultural transfer and the essence of developments, becoming a fundamental way of studying culture and its transformations. Thus, an important aim is the correlation of language phenomena with more general contact-induced culture change, including especially evolving forms of political, social and municipal organization in the native world, where the change is more salient. Breaking existing disciplinary boundaries in the humanities, the project embraces both indigenous and European perspectives, assuming that the innovation of studying both sides in a single framework and in the proposed time span is particularly promising in dealing with a notably two-sided, prolonged historical process. The complementary lines of research, native and Spanish, are expected to highlight and make understandable factors underlying and facilitating cultural convergence between them in different aspects of colonial life and beyond."
Summary
"At the core of this research proposal is the aim of reconstructing and understanding the nature, exact trajectories, mechanisms and implications of cross-cultural contact and transfers between Europeans and the native people of the Americas, focusing on, but not limited to, the Nahuatl-speaking zone of central Mexico. A major innovation of this project is to study this process of cross-cultural communication in its full historical depth, through the colonial and postcolonial eras up to the present day and encompassing different stages and types of contact. The meticulous and cross-disciplinary study of an extensive body of texts in Nahuatl (“Aztec”) and Spanish, complemented by present-day ethnolinguistic data, will make it possible to deduce and understand patterns across time and space in ways novel to existing scholarship, embracing both micro- and macroregional trends. The proposed research starts with identifying transfers in language, studied systematically through the creation of extensive databases, but leads to exploring the substance of cross-cultural transfer and the essence of developments, becoming a fundamental way of studying culture and its transformations. Thus, an important aim is the correlation of language phenomena with more general contact-induced culture change, including especially evolving forms of political, social and municipal organization in the native world, where the change is more salient. Breaking existing disciplinary boundaries in the humanities, the project embraces both indigenous and European perspectives, assuming that the innovation of studying both sides in a single framework and in the proposed time span is particularly promising in dealing with a notably two-sided, prolonged historical process. The complementary lines of research, native and Spanish, are expected to highlight and make understandable factors underlying and facilitating cultural convergence between them in different aspects of colonial life and beyond."
Max ERC Funding
1 318 840 €
Duration
Start date: 2012-12-01, End date: 2017-11-30
Project acronym ELWar
Project Electoral Legacies of War: Political Competition in Postwar Southeast Europe
Researcher (PI) Josip GLAURDIC
Host Institution (HI) UNIVERSITE DU LUXEMBOURG
Country Luxembourg
Call Details Starting Grant (StG), SH2, ERC-2016-STG
Summary We know remarkably little about the impact of war on political competition in postwar societies in spite of the fact that postwar elections have garnered tremendous interest from researchers in a variety of fields. That interest, however, has been limited to establishing the relationship between electoral democratization and the incidence of conflict. Voters’ and parties’ electoral behaviour after the immediate post‐conflict period have remained largely neglected by researchers. The proposed project will fill this gap in our understanding of electoral legacies of war by analysing the evolution of political competition over the course of more than two decades in the six postwar states of Southeast Europe: Bosnia-Herzegovina, Croatia, Kosovo, Macedonia, Montenegro, and Serbia. Organised around three thematic areas/levels of analysis – voters, parties, communities – the project will lead to a series of important contributions. Through a combination of public opinion research, oral histories, and the innovative method of matching of individual census entries, the project will answer to which extent postwar elections are decided by voters’ experiences and perceptions of the ended conflict, as opposed to their considerations of the parties’ peacetime economic platforms and performance in office. In-depth study of party documents and platforms, party relations with the organisations of the postwar civil sector, as well as interviews with party officials and activists will shed light on the influence of war on electoral strategies, policy preferences, and recruitment methods of postwar political parties. And a combination of large-N research on the level of the region’s municipalities and a set of paired comparisons of several communities in the different postwar communities in the region will help expose the mechanisms through which war becomes embedded into postwar political competition and thus continues to exert its influence even decades after the violence has ended.
Summary
We know remarkably little about the impact of war on political competition in postwar societies in spite of the fact that postwar elections have garnered tremendous interest from researchers in a variety of fields. That interest, however, has been limited to establishing the relationship between electoral democratization and the incidence of conflict. Voters’ and parties’ electoral behaviour after the immediate post‐conflict period have remained largely neglected by researchers. The proposed project will fill this gap in our understanding of electoral legacies of war by analysing the evolution of political competition over the course of more than two decades in the six postwar states of Southeast Europe: Bosnia-Herzegovina, Croatia, Kosovo, Macedonia, Montenegro, and Serbia. Organised around three thematic areas/levels of analysis – voters, parties, communities – the project will lead to a series of important contributions. Through a combination of public opinion research, oral histories, and the innovative method of matching of individual census entries, the project will answer to which extent postwar elections are decided by voters’ experiences and perceptions of the ended conflict, as opposed to their considerations of the parties’ peacetime economic platforms and performance in office. In-depth study of party documents and platforms, party relations with the organisations of the postwar civil sector, as well as interviews with party officials and activists will shed light on the influence of war on electoral strategies, policy preferences, and recruitment methods of postwar political parties. And a combination of large-N research on the level of the region’s municipalities and a set of paired comparisons of several communities in the different postwar communities in the region will help expose the mechanisms through which war becomes embedded into postwar political competition and thus continues to exert its influence even decades after the violence has ended.
Max ERC Funding
1 499 788 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym MitoRepairosome
Project Dissecting the mechanism of DNA repair in human mitochondria
Researcher (PI) Michal Szymanski
Host Institution (HI) UNIWERSYTET GDANSKI
Country Poland
Call Details Starting Grant (StG), LS1, ERC-2019-STG
Summary In mammalian cells genetic information is stored in two compartments: in the nucleus and in the mitochondria. DNA in mitochondria (mtDNA), just like in theIn mammalian cells genetic information is stored in two locations: in the nucleus and in mitochondria. DNA in mitochondria, just like in the nucleus, must be faithfully copied and mistakes (i.e. mutations due to exogenous and endogenous DNA damaging agents) lead to formation of DNA lesions. Persistence of these DNA lesions leads to genomic instability and human diseases like cardiovascular, skeletal muscular and neurological disorders, cancer as well as normal aging process. Mitochondrial DNA (mtDNA) is anchored to the inner mitochondrial membrane thus is in a close proximity to the electron transport chain and is subjected to a constant attack by reactive oxygen species (ROS), generated as byproducts of oxidative phosphorylation (OXPHOS). As a result mitochondria must have a robust DNA repair mechanism which becomes particularly important in non-dividing cells. It is accepted that DNA base excision repair (BER) pathway is a major defense mechanism against oxidative damage in human mitochondria. Aptly localized on mitochondrial inner membrane, mitochondrial BER enzymes: catalytic subunit of DNA polymerase γ (PolγA) along with its accessory subunit, DNA polymerase γ (PolγB), inner-membrane 5'-exo/endonuclease (EXOG), Apurinic/apyrimidinic endonuclease 1 (APE1) and Ligase 3 (Lig3) form a membrane-bound, high molecular weight, complexes called “mitochondrial repairosome”, capable of carrying out complete DNA repair. Although BER can be readily detected in mitochondria and major components have been identified, the spatial-temporal organization of mitochondrial repairosome and molecular mechanism by which mtDNA is repaired is not well understood. The goal of this research project is to provide fundamental mechanistic insights into the assembly, composition, activities and structures of human mitochondrial repairosome.
Summary
In mammalian cells genetic information is stored in two compartments: in the nucleus and in the mitochondria. DNA in mitochondria (mtDNA), just like in theIn mammalian cells genetic information is stored in two locations: in the nucleus and in mitochondria. DNA in mitochondria, just like in the nucleus, must be faithfully copied and mistakes (i.e. mutations due to exogenous and endogenous DNA damaging agents) lead to formation of DNA lesions. Persistence of these DNA lesions leads to genomic instability and human diseases like cardiovascular, skeletal muscular and neurological disorders, cancer as well as normal aging process. Mitochondrial DNA (mtDNA) is anchored to the inner mitochondrial membrane thus is in a close proximity to the electron transport chain and is subjected to a constant attack by reactive oxygen species (ROS), generated as byproducts of oxidative phosphorylation (OXPHOS). As a result mitochondria must have a robust DNA repair mechanism which becomes particularly important in non-dividing cells. It is accepted that DNA base excision repair (BER) pathway is a major defense mechanism against oxidative damage in human mitochondria. Aptly localized on mitochondrial inner membrane, mitochondrial BER enzymes: catalytic subunit of DNA polymerase γ (PolγA) along with its accessory subunit, DNA polymerase γ (PolγB), inner-membrane 5'-exo/endonuclease (EXOG), Apurinic/apyrimidinic endonuclease 1 (APE1) and Ligase 3 (Lig3) form a membrane-bound, high molecular weight, complexes called “mitochondrial repairosome”, capable of carrying out complete DNA repair. Although BER can be readily detected in mitochondria and major components have been identified, the spatial-temporal organization of mitochondrial repairosome and molecular mechanism by which mtDNA is repaired is not well understood. The goal of this research project is to provide fundamental mechanistic insights into the assembly, composition, activities and structures of human mitochondrial repairosome.
Max ERC Funding
1 500 000 €
Duration
Start date: 2020-02-01, End date: 2025-01-31
Project acronym NERCOMP
Project Structural studies of Nucleotide Excision Repair complexes
Researcher (PI) Marcin Nowotny
Host Institution (HI) INTERNATIONAL INSTITUTE OF MOLECULAR AND CELL BIOLOGY
Country Poland
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary "DNA damage caused by chemical and physical factors can lead to detrimental effects to the cell and must be corrected. One of the primary pathways to achieve this repair is nucleotide excision repair (NER). In NER, the DNA damage is first located, a stretch of bases harboring the lesion is removed, and the gap is filled by a DNA polymerase. The unique feature of NER is its ability to correct a wide spectrum of DNA modifications of different sizes and chemical structures.
The aim of the project is to structurally and biochemically characterize protein complexes involved in NER pathways in bacteria and eukaryotes.
In bacterial NER, a complex of UvrA and UvrB proteins locates the damage and verifies its presence. In the first part of the project we plan to determine the crystal and small-angle X-ray scattering (SAXS) structures of a UvrA-UvrB-DNA complex to elucidate the details of the mechanism of the first steps of bacterial NER.
In eukaryotic NER, the 3′ incision is executed by XPG/Rad2 protein. Currently, no structural information is available for this protein. In the second part of the project, we plan to solve the crystal structures of XPG/Rad2 nuclease in apo form and in complex with the DNA substrate to elucidate the mechanism of the 3′ cut. We also plan to determine the structure of XPG/Rad2 in complex with the XPG/Rad2-binding domain from the p62 component of TFIIH, which will be an important building block for the determination of the architecture of the eukaryotic NER pre-incision complex.
The third part of the project will elucidate the structure and mechanism of the Rad16-Rad7 yeast NER complex. It is implicated in numerous stages of NER, from damage detection to ubiquitination of other NER components. We plan to solve the crystal structures of the Rad16-Rad7 alone and in complexes with DNA or partner protein Abf1 to elucidate the mechanisms of various activities of Rad16-Rad7 and help design experiments that could test the in vivo function of this complex."
Summary
"DNA damage caused by chemical and physical factors can lead to detrimental effects to the cell and must be corrected. One of the primary pathways to achieve this repair is nucleotide excision repair (NER). In NER, the DNA damage is first located, a stretch of bases harboring the lesion is removed, and the gap is filled by a DNA polymerase. The unique feature of NER is its ability to correct a wide spectrum of DNA modifications of different sizes and chemical structures.
The aim of the project is to structurally and biochemically characterize protein complexes involved in NER pathways in bacteria and eukaryotes.
In bacterial NER, a complex of UvrA and UvrB proteins locates the damage and verifies its presence. In the first part of the project we plan to determine the crystal and small-angle X-ray scattering (SAXS) structures of a UvrA-UvrB-DNA complex to elucidate the details of the mechanism of the first steps of bacterial NER.
In eukaryotic NER, the 3′ incision is executed by XPG/Rad2 protein. Currently, no structural information is available for this protein. In the second part of the project, we plan to solve the crystal structures of XPG/Rad2 nuclease in apo form and in complex with the DNA substrate to elucidate the mechanism of the 3′ cut. We also plan to determine the structure of XPG/Rad2 in complex with the XPG/Rad2-binding domain from the p62 component of TFIIH, which will be an important building block for the determination of the architecture of the eukaryotic NER pre-incision complex.
The third part of the project will elucidate the structure and mechanism of the Rad16-Rad7 yeast NER complex. It is implicated in numerous stages of NER, from damage detection to ubiquitination of other NER components. We plan to solve the crystal structures of the Rad16-Rad7 alone and in complexes with DNA or partner protein Abf1 to elucidate the mechanisms of various activities of Rad16-Rad7 and help design experiments that could test the in vivo function of this complex."
Max ERC Funding
1 498 000 €
Duration
Start date: 2012-01-01, End date: 2017-12-31
Project acronym PAAL
Project Practical Approximation Algorithms
Researcher (PI) Piotr Sankowski
Host Institution (HI) UNIWERSYTET WARSZAWSKI
Country Poland
Call Details Starting Grant (StG), PE6, ERC-2010-StG_20091028
Summary The goal of this proposal is the development and study of practical approximation algorithms. We will base our study on
theoretical models that can describe requirements for algorithms that make them practically efficient. We plan to develop an
efficient and useful programming library of approximation algorithms.
Our research on approximation algorithms will be concentrated on two main topics:
- multi-problem optimization, when the solution has to be composed out of different problems that need to interact,
- interplay between regular and random structure of network that could allow construction of good approximation algorithms.
The above concepts try to capture the notion of effective algorithms. It has to be underlined that they were not studied before.
The practical importance of these problems will be verified by the accompanying work on generic programming concepts
for approximation algorithms. These concepts will form the basis of universal library that will include Web algorithms and
algorithms for physical applications.
Summary
The goal of this proposal is the development and study of practical approximation algorithms. We will base our study on
theoretical models that can describe requirements for algorithms that make them practically efficient. We plan to develop an
efficient and useful programming library of approximation algorithms.
Our research on approximation algorithms will be concentrated on two main topics:
- multi-problem optimization, when the solution has to be composed out of different problems that need to interact,
- interplay between regular and random structure of network that could allow construction of good approximation algorithms.
The above concepts try to capture the notion of effective algorithms. It has to be underlined that they were not studied before.
The practical importance of these problems will be verified by the accompanying work on generic programming concepts
for approximation algorithms. These concepts will form the basis of universal library that will include Web algorithms and
algorithms for physical applications.
Max ERC Funding
1 000 000 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
Project acronym PAPS&PUPS
Project Regulation of Gene Expression by non-canonical poly(A) and poly(U) polymerases
Researcher (PI) Andrzej Dziembowski
Host Institution (HI) INSTYTUT BIOCHEMII I BIOFIZYKI POLSKIEJ AKADEMII NAUK
Country Poland
Call Details Starting Grant (StG), LS1, ERC-2012-StG_20111109
Summary In eukaryotes, almost all RNA molecules are processed at their 3’ ends and most mRNAs are polyadenylated in the nucleus by canonical poly(A) polymerases (PAPs). Recently, several new non-canonical poly(A) (ncPAPs) and poly(U) polymerases (PUPs) have been discovered that have more specific regulatory roles. In contrast to canonical ones, their functions are more diverse; some induce RNA decay while others, especially cytoplasmic ncPAPs, activate translationally dormant deadenylated mRNAs. Knowledge about ncPAPs and PUPs is very scarce and there are crucial questions about their functions that need to be addressed.
The project has 3 parts:
1) Functional analysis of FAM46 proteins, which, according to our preliminary data, constitute a new family of active poly(A) polymerases. FAM46C is frequently mutated in myelomas and mutations in its mouse orthologue cause anaemia, thus demonstrating important biological functions of this unexplored family of proteins.
2) Elucidation of the functions of all known vertebrate ncPAPs and PUPs (7 previously known and 4 members of FAM46 family) using the chicken DT40 cell line as a model system. DT40 has an exceptionally high rate of homologous recombination, allowing easy gene targeting and generation of multiple knockouts that facilitate the study of proteins with overlapping functions.
3) Cytoplasmic polyadenylation of dormant mRNA molecules activates translation in neurons, gametes and reticulocytes. In neurons, it occurs in axons and dendrites following synaptic stimulation while in oocytes, it is induced by progesterone. The exact impact on gene expression is not well defined due to a lack of technologies identifying cytoplasmically polyadenylated transcripts. We will develop a novel detection method for ongoing RNA polyadenylation to assess the biological significance of cytoplasmic polyadenylation. This part of the project will be developed using mouse synaptoneurosomes and then transferred to reticulocytes and possibly oocytes.
Summary
In eukaryotes, almost all RNA molecules are processed at their 3’ ends and most mRNAs are polyadenylated in the nucleus by canonical poly(A) polymerases (PAPs). Recently, several new non-canonical poly(A) (ncPAPs) and poly(U) polymerases (PUPs) have been discovered that have more specific regulatory roles. In contrast to canonical ones, their functions are more diverse; some induce RNA decay while others, especially cytoplasmic ncPAPs, activate translationally dormant deadenylated mRNAs. Knowledge about ncPAPs and PUPs is very scarce and there are crucial questions about their functions that need to be addressed.
The project has 3 parts:
1) Functional analysis of FAM46 proteins, which, according to our preliminary data, constitute a new family of active poly(A) polymerases. FAM46C is frequently mutated in myelomas and mutations in its mouse orthologue cause anaemia, thus demonstrating important biological functions of this unexplored family of proteins.
2) Elucidation of the functions of all known vertebrate ncPAPs and PUPs (7 previously known and 4 members of FAM46 family) using the chicken DT40 cell line as a model system. DT40 has an exceptionally high rate of homologous recombination, allowing easy gene targeting and generation of multiple knockouts that facilitate the study of proteins with overlapping functions.
3) Cytoplasmic polyadenylation of dormant mRNA molecules activates translation in neurons, gametes and reticulocytes. In neurons, it occurs in axons and dendrites following synaptic stimulation while in oocytes, it is induced by progesterone. The exact impact on gene expression is not well defined due to a lack of technologies identifying cytoplasmically polyadenylated transcripts. We will develop a novel detection method for ongoing RNA polyadenylation to assess the biological significance of cytoplasmic polyadenylation. This part of the project will be developed using mouse synaptoneurosomes and then transferred to reticulocytes and possibly oocytes.
Max ERC Funding
1 500 000 €
Duration
Start date: 2013-02-01, End date: 2019-01-31
Project acronym PGPE
Project Public Goods through Private Eyes. Exploring Citizens' Attitudes to Public Goods and the State in Central Eastern Europe
Researcher (PI) Natalia Garner
Host Institution (HI) UNIWERSYTET WARSZAWSKI
Country Poland
Call Details Starting Grant (StG), SH2, ERC-2009-StG
Summary Post-communist states of Central and Eastern Europe form a particularly challenging context for public goods production, due to the communist legacies as well as experiences of transformation. Drawing on theory and research available in political science, sociology and economics, this multi-disciplinary, comparative project will formulate and test an extensive model of public goods oriented behaviour and its determinants in the context of post-communist countries of CEE. The key objectives of this proposed project are to: (i) design and execute a full-scale cross-national survey on the determinants of public's attitudes and behaviour towards public goods; and (ii) combine these data with a wider range of existing indicators, relating to institutional design, social changes, political and economic reforms as well as historical legacies, in the context of post-communist Central Eastern Europe. Its fundamental aim, therefore, is to generate knowledge on the key determinants of democratic governance and democratic deepening in new democracies. This knowledge will allow to understand how citizens and governments of transition countries can work together towards a greater social, political, economic and environmental sustainability.
Summary
Post-communist states of Central and Eastern Europe form a particularly challenging context for public goods production, due to the communist legacies as well as experiences of transformation. Drawing on theory and research available in political science, sociology and economics, this multi-disciplinary, comparative project will formulate and test an extensive model of public goods oriented behaviour and its determinants in the context of post-communist countries of CEE. The key objectives of this proposed project are to: (i) design and execute a full-scale cross-national survey on the determinants of public's attitudes and behaviour towards public goods; and (ii) combine these data with a wider range of existing indicators, relating to institutional design, social changes, political and economic reforms as well as historical legacies, in the context of post-communist Central Eastern Europe. Its fundamental aim, therefore, is to generate knowledge on the key determinants of democratic governance and democratic deepening in new democracies. This knowledge will allow to understand how citizens and governments of transition countries can work together towards a greater social, political, economic and environmental sustainability.
Max ERC Funding
1 730 000 €
Duration
Start date: 2009-12-01, End date: 2014-11-30
Project acronym RNA+P=123D
Project Breaking the code of RNA sequence-structure-function relationships: New strategies and tools for modelling and engineering of RNA and RNA-protein complexes
Researcher (PI) Janusz Marek Bujnicki
Host Institution (HI) INTERNATIONAL INSTITUTE OF MOLECULAR AND CELL BIOLOGY
Country Poland
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary Ribonucleic acid (RNA) is a large class of macromolecules that plays a key role in the communication of biological information between DNA and proteins. RNAs have been also shown to perform enzymatic catalysis. Recently, numerous new RNAs have been identified and shown to perform essential regulatory roles in cells.
As with proteins, the function of RNA depends on its structure, which in turn is encoded in the linear sequence. The secondary structure of RNA is defined by canonical base pairs, while the tertiary (3D) structure is formed mostly by non-canonical base pairs that form three-dimensional motifs. RNA is similar to proteins in that the development of methods for 3D structure prediction is absolutely essential to functionally interpret the information encoded in the primary sequence of genes. For proteins there are many freely available methods for automated protein 3D structure prediction that produce reasonably accurate and useful models. There are also methods for objective assessment of the protein model quality. However, there are no such methods for automated 3D structure modelling of RNA. There are only methods for RNA secondary structure prediction and a few methods for manual 3D modelling, but no automated methods for comparative modelling, fold-recognition of RNA, and evaluation of models. Only recently a few methods for de novo folding of RNA appeared, but they can provide useful models only for very short molecules.
Recently, inspired by methodology for protein modelling, we have developed prototype tools for both comparative (template-based) and de novo (template-free) modelling of RNA, which allow for building models for very large RNA molecules. These tools will be further optimized and tested. The major goal is to developed tools for RNA modelling to the level of existing protein-modelling methods and to combine RNA and protein-centric methods to allow multiscale modelling of protein-nucleic acid complexes, either with or without the aid of experimental data. This proposal also includes the development of methods for the assessment of model quality and benchmarking of methods. The software tools and the theoretical predictions will be extensively tested (also by experimental verification of models), optimized and applied to biologically and medically relevant RNAs and complexes.
In one sentence: The aim of this project is to use bioinformatics and experimental methods to crack the code of sequence-structure relationships in RNA and RNA-protein complexes and to revolutionise the field of RNA & RNP modelling and structure/function analyses.
Summary
Ribonucleic acid (RNA) is a large class of macromolecules that plays a key role in the communication of biological information between DNA and proteins. RNAs have been also shown to perform enzymatic catalysis. Recently, numerous new RNAs have been identified and shown to perform essential regulatory roles in cells.
As with proteins, the function of RNA depends on its structure, which in turn is encoded in the linear sequence. The secondary structure of RNA is defined by canonical base pairs, while the tertiary (3D) structure is formed mostly by non-canonical base pairs that form three-dimensional motifs. RNA is similar to proteins in that the development of methods for 3D structure prediction is absolutely essential to functionally interpret the information encoded in the primary sequence of genes. For proteins there are many freely available methods for automated protein 3D structure prediction that produce reasonably accurate and useful models. There are also methods for objective assessment of the protein model quality. However, there are no such methods for automated 3D structure modelling of RNA. There are only methods for RNA secondary structure prediction and a few methods for manual 3D modelling, but no automated methods for comparative modelling, fold-recognition of RNA, and evaluation of models. Only recently a few methods for de novo folding of RNA appeared, but they can provide useful models only for very short molecules.
Recently, inspired by methodology for protein modelling, we have developed prototype tools for both comparative (template-based) and de novo (template-free) modelling of RNA, which allow for building models for very large RNA molecules. These tools will be further optimized and tested. The major goal is to developed tools for RNA modelling to the level of existing protein-modelling methods and to combine RNA and protein-centric methods to allow multiscale modelling of protein-nucleic acid complexes, either with or without the aid of experimental data. This proposal also includes the development of methods for the assessment of model quality and benchmarking of methods. The software tools and the theoretical predictions will be extensively tested (also by experimental verification of models), optimized and applied to biologically and medically relevant RNAs and complexes.
In one sentence: The aim of this project is to use bioinformatics and experimental methods to crack the code of sequence-structure relationships in RNA and RNA-protein complexes and to revolutionise the field of RNA & RNP modelling and structure/function analyses.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-01-01, End date: 2015-12-31
