Project acronym FORCEMAP
Project Intramolecular force mapping of enzymes in action: the role of strain in motor mechanisms
Researcher (PI) András Málnási-Csizmadia
Host Institution (HI) EOTVOS LORAND TUDOMANYEGYETEM
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary A fundamental but unexplored problem in biology is whether and how enzymes use mechanical strain during their functioning. It is now evident that the knowledge of atomic structures and chemical interactions is not sufficient to understand the intricate mechanisms underlying enzyme specificity and efficiency. Several lines of evidence suggest that mechanical effects play crucial roles in enzyme activity. Therefore we aim to create detailed force maps that reveal how the intramolecular distribution of mechanical strains changes during the enzyme cycle and how these rearrangements drive the enzyme processes. The applicability of current nanotechniques for the investigation of this problem is limited because they do not allow simultaneous measurement of mechanical and enzymatic parameters. Thus we seek to open new avenues of research by developing site-specific sensors and passive or photoinducible molecular springs to measure force-dependent chemical/structural changes with high spatiotemporal resolution in myosin. Since force perturbations occur very rapidly, we are able to combine experimental studies with quasi-realistic in silico simulations to describe the physical background of enzyme function. We expect that our research will yield fundamental insights into the role of intramolecular strains in enzymes and thus greatly aid the design and control of enzyme processes (specificity, activity, regulation). Our studies may also lead to new paradigms in the understanding of motor systems.
Summary
A fundamental but unexplored problem in biology is whether and how enzymes use mechanical strain during their functioning. It is now evident that the knowledge of atomic structures and chemical interactions is not sufficient to understand the intricate mechanisms underlying enzyme specificity and efficiency. Several lines of evidence suggest that mechanical effects play crucial roles in enzyme activity. Therefore we aim to create detailed force maps that reveal how the intramolecular distribution of mechanical strains changes during the enzyme cycle and how these rearrangements drive the enzyme processes. The applicability of current nanotechniques for the investigation of this problem is limited because they do not allow simultaneous measurement of mechanical and enzymatic parameters. Thus we seek to open new avenues of research by developing site-specific sensors and passive or photoinducible molecular springs to measure force-dependent chemical/structural changes with high spatiotemporal resolution in myosin. Since force perturbations occur very rapidly, we are able to combine experimental studies with quasi-realistic in silico simulations to describe the physical background of enzyme function. We expect that our research will yield fundamental insights into the role of intramolecular strains in enzymes and thus greatly aid the design and control of enzyme processes (specificity, activity, regulation). Our studies may also lead to new paradigms in the understanding of motor systems.
Max ERC Funding
750 000 €
Duration
Start date: 2008-09-01, End date: 2014-08-31
Project acronym MOLINFLAM
Project Molecular dissection of inflammatory pathways
Researcher (PI) Attila Mocsai
Host Institution (HI) SEMMELWEIS EGYETEM
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary Inflammatory diseases are highly prevalent, often chronic diseases that cause diminished quality of life and are connected with major causes of death in Western societies. Despite their societal impact, their pathomechanism is incompletely understood, hindering development of novel therapeutic strategies. In particular, little is known about the intracellular signal transduction processes involved in the tissue destruction phase of aggressive autoimmune diseases such as rheumatoid arthritis. The present proposal aims to clarify this issue using in vivo and in vitro studies on genetically manipulated mice. During the proposed studies, mice deficient in various signal transduction molecules such as Syk, PLCg2, Gab2 and p190 RhoGAPs will be used to test their contribution to inflammatory responses. In vitro studies will test the activation of major effector cells of inflammation (neutrophils, macrophages and osteoclasts) while in vivo studies will utilize mouse models such as autoantibody- and cytokine-induced inflammatory arthritis or autoantibody-induced glomerulonephritis. Further studies will be performed to test the contribution of the above signaling molecules to disease pathogenesis in a lineage-restricted manner, using the Cre-lox approach. Finally, wild type and mutant versions of the signaling molecules tested will be retrovirally re-expressed into the relevant knockout hematopoietic stem cells in vivo to allow structure-function studies during in vivo inflammation. Two novel transgenic strains and a knock-in (floxed) mutant will also be generated during the course of the project. Using state-of-the-art approaches and techniques, this project will provide information at unprecedented molecular detail on signal transduction mechanisms involved in inflammatory diseases, and is expected to point to possible future targets of novel anti-inflammatory therapies.
Summary
Inflammatory diseases are highly prevalent, often chronic diseases that cause diminished quality of life and are connected with major causes of death in Western societies. Despite their societal impact, their pathomechanism is incompletely understood, hindering development of novel therapeutic strategies. In particular, little is known about the intracellular signal transduction processes involved in the tissue destruction phase of aggressive autoimmune diseases such as rheumatoid arthritis. The present proposal aims to clarify this issue using in vivo and in vitro studies on genetically manipulated mice. During the proposed studies, mice deficient in various signal transduction molecules such as Syk, PLCg2, Gab2 and p190 RhoGAPs will be used to test their contribution to inflammatory responses. In vitro studies will test the activation of major effector cells of inflammation (neutrophils, macrophages and osteoclasts) while in vivo studies will utilize mouse models such as autoantibody- and cytokine-induced inflammatory arthritis or autoantibody-induced glomerulonephritis. Further studies will be performed to test the contribution of the above signaling molecules to disease pathogenesis in a lineage-restricted manner, using the Cre-lox approach. Finally, wild type and mutant versions of the signaling molecules tested will be retrovirally re-expressed into the relevant knockout hematopoietic stem cells in vivo to allow structure-function studies during in vivo inflammation. Two novel transgenic strains and a knock-in (floxed) mutant will also be generated during the course of the project. Using state-of-the-art approaches and techniques, this project will provide information at unprecedented molecular detail on signal transduction mechanisms involved in inflammatory diseases, and is expected to point to possible future targets of novel anti-inflammatory therapies.
Max ERC Funding
1 200 000 €
Duration
Start date: 2008-10-01, End date: 2014-03-31
Project acronym NETWORK EVOLUTION
Project Integrated evolutionary analyses of genetic and drug interaction networks in yeast
Researcher (PI) Csaba Pal
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA SZEGEDIBIOLOGIAI KUTATOKOZPONT
Call Details Starting Grant (StG), LS5, ERC-2007-StG
Summary The ability of cellular systems to adapt to genetic and environmental perturbations is a fundamental but poorly understood process both at the molecular and evolutionary level. There are both physiological and evolutionary reasonings why mutations often have limited impact on cellular growth. First, perturbations that hit one target often have no effect on the overall performance of a complex system (such as metabolic networks), as perturbations can be adjusted by reorganizing fluxes in metabolic networks, or changing regulation and expression of genes. Second, due to the fast evolvability of microbes, the effect of a perturbation can readily be alleviated by the evolution of compensatory mutations at other sites of the network. Understanding the extent of intrinsic and evolved robustness in cellular systems demands integrated analyses that combine functional genomics and computational systems biology with microbial evolutionary experiments. In collaboration with several leading research teams in the field, we plan to investigate the following issues. First, we will ask how accurately genome-scale metabolic network models can predict the impact of genetic deletions and other non-heritable perturbations. Second, to understand how the impact of genetic and drug perturbations can be mitigated during evolution, we will pursue a large-scale lab evolutionary protocol, and compare the results with predictions of computational models. Our work may suggest avenues of research on the general rules of acquired drug resistance in microbes.
Summary
The ability of cellular systems to adapt to genetic and environmental perturbations is a fundamental but poorly understood process both at the molecular and evolutionary level. There are both physiological and evolutionary reasonings why mutations often have limited impact on cellular growth. First, perturbations that hit one target often have no effect on the overall performance of a complex system (such as metabolic networks), as perturbations can be adjusted by reorganizing fluxes in metabolic networks, or changing regulation and expression of genes. Second, due to the fast evolvability of microbes, the effect of a perturbation can readily be alleviated by the evolution of compensatory mutations at other sites of the network. Understanding the extent of intrinsic and evolved robustness in cellular systems demands integrated analyses that combine functional genomics and computational systems biology with microbial evolutionary experiments. In collaboration with several leading research teams in the field, we plan to investigate the following issues. First, we will ask how accurately genome-scale metabolic network models can predict the impact of genetic deletions and other non-heritable perturbations. Second, to understand how the impact of genetic and drug perturbations can be mitigated during evolution, we will pursue a large-scale lab evolutionary protocol, and compare the results with predictions of computational models. Our work may suggest avenues of research on the general rules of acquired drug resistance in microbes.
Max ERC Funding
1 280 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym ZARAH
Project Women’s labour activism in Eastern Europe and transnationally, from the age of empires to the late 20th century
Researcher (PI) Susan Carin Zimmermann
Host Institution (HI) KOZEP-EUROPAI EGYETEM
Call Details Advanced Grant (AdG), SH6, ERC-2018-ADG
Summary ZARAH explores the history of women’s labour activism and organizing to improve labour conditions and life circumstances of lower and working class women and their communities—moving these women from the margins of labour, gender, and European history to the centre of historical study.
ZARAH’s research rationale is rooted in the interest in the interaction of gender, class, and other dimensions of difference (e.g. ethnicity and religion) as forces that shaped women’s activism. It addresses the gender bias in labour history, the class bias in gender history, and the regional bias in European history. ZARAH conceives of women’s labour activism as emerging from the confluence of local, nation-wide, border-crossing and international initiatives, interactions and networking. It studies this activism in the Austro-Hungarian and Ottoman Empires, the post-imperial nation states, and during the Cold War and the years thereafter. Employing a long-term and trans-regional perspective, ZARAH highlights how a history of numerous social upheavals, and changing borders and political systems shaped the agency of the women studied, and examines their contribution to the struggle for socio-economic inclusion and the making of gender-, labour-, and social policies.
ZARAH comprises, in addition to the PI, an international group of nine post-doctoral and doctoral researchers at CEU, distinguished by their excellent command of the history and languages of the region. Research rationale, research questions, and methodological framework were developed through an intensive exploratory research phase (2016–2017). ZARAH is a pioneering project that consists of a web of component and collaborative studies, which include all relevant groups of activists and activisms, span the whole region, and cover the period between the 1880s and the 1990s. It will generate key research resources that are available to all students and scholars, and will set the stage for research for a long time to come.
Summary
ZARAH explores the history of women’s labour activism and organizing to improve labour conditions and life circumstances of lower and working class women and their communities—moving these women from the margins of labour, gender, and European history to the centre of historical study.
ZARAH’s research rationale is rooted in the interest in the interaction of gender, class, and other dimensions of difference (e.g. ethnicity and religion) as forces that shaped women’s activism. It addresses the gender bias in labour history, the class bias in gender history, and the regional bias in European history. ZARAH conceives of women’s labour activism as emerging from the confluence of local, nation-wide, border-crossing and international initiatives, interactions and networking. It studies this activism in the Austro-Hungarian and Ottoman Empires, the post-imperial nation states, and during the Cold War and the years thereafter. Employing a long-term and trans-regional perspective, ZARAH highlights how a history of numerous social upheavals, and changing borders and political systems shaped the agency of the women studied, and examines their contribution to the struggle for socio-economic inclusion and the making of gender-, labour-, and social policies.
ZARAH comprises, in addition to the PI, an international group of nine post-doctoral and doctoral researchers at CEU, distinguished by their excellent command of the history and languages of the region. Research rationale, research questions, and methodological framework were developed through an intensive exploratory research phase (2016–2017). ZARAH is a pioneering project that consists of a web of component and collaborative studies, which include all relevant groups of activists and activisms, span the whole region, and cover the period between the 1880s and the 1990s. It will generate key research resources that are available to all students and scholars, and will set the stage for research for a long time to come.
Max ERC Funding
2 499 947 €
Duration
Start date: 2020-02-01, End date: 2025-01-31
