Project acronym NewSpindleForce
Project A new class of microtubules in the spindle exerting forces on kinetochores
Researcher (PI) Iva Marija Tolic
Host Institution (HI) RUDER BOSKOVIC INSTITUTE
Call Details Consolidator Grant (CoG), LS3, ERC-2014-CoG
Summary At the onset of division the cell forms a spindle, a micro-machine made of microtubules, which divide the chromosomes by pulling on kinetochores, protein complexes on the chromosome. The central question in the field is how accurate chromosome segregation results from the interactions between kinetochores, microtubules and the associated proteins. According to the current paradigm, the forces on kinetochores are produced by k-fibers, bundles of microtubules extending between the spindle pole and the kinetochore. The proposed project is built upon a groundbreaking hypothesis that a new class of microtubules, which we term bridging microtubules, bridge sister kinetochores. Our preliminary results show that bridging microtubules are responsible for the positioning of kinetochores in HeLa and PtK1 cells. Bridging microtubules have not been studied before because this requires cutting-edge microscopy and laser microsurgery techniques. By applying these methods, with which I have extensive expertise, we will determine the organization of these microtubules, identify the proteins that link them with k-fibers, and uncover where and how the forces for kinetochore positioning and movement are generated. My strength is in taking an interdisciplinary approach, which I will use in this project by combining laser microsurgery with genetic perturbations, quantitative measurements of the responses and comparison with theoretical models. Understanding the role of bridging microtubules in force generation and chromosome movements will not only shed light on the mechanism of chromosome segregation, but may also increase the potential of mitotic anticancer strategies, as the spindle is a major target for chemotherapy. The proposed ERC funding is essential for the success of these timely and ambitious experiments, allowing me to strengthen my position as an international leader in research on cell division, thereby increasing Europe's foremost position in this field.
Summary
At the onset of division the cell forms a spindle, a micro-machine made of microtubules, which divide the chromosomes by pulling on kinetochores, protein complexes on the chromosome. The central question in the field is how accurate chromosome segregation results from the interactions between kinetochores, microtubules and the associated proteins. According to the current paradigm, the forces on kinetochores are produced by k-fibers, bundles of microtubules extending between the spindle pole and the kinetochore. The proposed project is built upon a groundbreaking hypothesis that a new class of microtubules, which we term bridging microtubules, bridge sister kinetochores. Our preliminary results show that bridging microtubules are responsible for the positioning of kinetochores in HeLa and PtK1 cells. Bridging microtubules have not been studied before because this requires cutting-edge microscopy and laser microsurgery techniques. By applying these methods, with which I have extensive expertise, we will determine the organization of these microtubules, identify the proteins that link them with k-fibers, and uncover where and how the forces for kinetochore positioning and movement are generated. My strength is in taking an interdisciplinary approach, which I will use in this project by combining laser microsurgery with genetic perturbations, quantitative measurements of the responses and comparison with theoretical models. Understanding the role of bridging microtubules in force generation and chromosome movements will not only shed light on the mechanism of chromosome segregation, but may also increase the potential of mitotic anticancer strategies, as the spindle is a major target for chemotherapy. The proposed ERC funding is essential for the success of these timely and ambitious experiments, allowing me to strengthen my position as an international leader in research on cell division, thereby increasing Europe's foremost position in this field.
Max ERC Funding
2 150 000 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym PreLog
Project Precursors of logical reasoning in human infants
Researcher (PI) Erno Teglas
Host Institution (HI) KOZEP-EUROPAI EGYETEM
Call Details Starting Grant (StG), SH4, ERC-2014-STG
Summary There is no other field that is more controversial in psychology than that of human reasoning. This project advances a novel theoretical framework focused on the nature and the origins of rationality and could potentially resolve some of these controversies. Theories targeting the mechanisms that allow rational inferences have defined rationality as a function of how much reasoning adheres to formal rules of probability calculus and logic. Classical research with adults and older children collected a large amount of data both in favor and against human rationality, suggesting that reasoning abilities follow a slow maturation. Recent findings on infants’ probabilistic reasoning, including my own earlier research, however, do not support this view. Already preverbal infants seem to form expectations about probabilistic events in accordance with Bayesian rules of inference (Téglás et al, 2011). Here I argue for a similar paradigm change in a related domain, that of deductive reasoning.
In contrast to earlier accounts, I propose that even preverbal infants may possess a core set of logical operations that empower them with sophisticated inferential abilities. First, I focus on the representational precursors of this competence. I argue that infants recruit specific abilities to exploit the conceptual structure of specific event categories that enable them to form logical representations. Thus, information could be stored in a format that can potentially serve as input for subsequent inferences. Further, I will investigate infants’ core logical operations and test how they integrate multiple steps of inferences. This system - indispensable for integrating different bits of knowledge - helps infants to discover information that was not actually present in the input. Such investigations, informed also by adequate neuropsychological evidence would thus contribute to understand the unique nature of human rationality.
Summary
There is no other field that is more controversial in psychology than that of human reasoning. This project advances a novel theoretical framework focused on the nature and the origins of rationality and could potentially resolve some of these controversies. Theories targeting the mechanisms that allow rational inferences have defined rationality as a function of how much reasoning adheres to formal rules of probability calculus and logic. Classical research with adults and older children collected a large amount of data both in favor and against human rationality, suggesting that reasoning abilities follow a slow maturation. Recent findings on infants’ probabilistic reasoning, including my own earlier research, however, do not support this view. Already preverbal infants seem to form expectations about probabilistic events in accordance with Bayesian rules of inference (Téglás et al, 2011). Here I argue for a similar paradigm change in a related domain, that of deductive reasoning.
In contrast to earlier accounts, I propose that even preverbal infants may possess a core set of logical operations that empower them with sophisticated inferential abilities. First, I focus on the representational precursors of this competence. I argue that infants recruit specific abilities to exploit the conceptual structure of specific event categories that enable them to form logical representations. Thus, information could be stored in a format that can potentially serve as input for subsequent inferences. Further, I will investigate infants’ core logical operations and test how they integrate multiple steps of inferences. This system - indispensable for integrating different bits of knowledge - helps infants to discover information that was not actually present in the input. Such investigations, informed also by adequate neuropsychological evidence would thus contribute to understand the unique nature of human rationality.
Max ERC Funding
1 498 137 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym resistance evolution
Project Bacterial evolution of hypersensitivity and resistance against antimicrobial peptides
Researcher (PI) Csaba Pal
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA SZEGEDIBIOLOGIAI KUTATOKOZPONT
Call Details Consolidator Grant (CoG), LS8, ERC-2014-CoG
Summary Evolution of resistance towards a single drug simultaneously increases (cross-resistance) or decreases (collateral sensitivity) fitness to multiple other antimicrobial agents. The molecular mechanisms driving cross-resistance are relatively well described, but it remains largely unclear how frequently does genetic adaptation to a single drug increase the sensitivity to others and what the underlying molecular mechanisms of collateral sensitivity are. This proposal focuses on studying the bacterial evolution of resistance and collateral sensitivity against antimicrobial peptides (AMPs). Beyond their modulatory roles in the immune system, these naturally occurring peptides provide protection against pathogenic microbes, and are considered as promising novel alternatives to traditional antibiotics. However, there are concerns that evolution against therapeutic AMPs can readily develop and as a by-product this might compromise natural immunity. Our knowledge of these issues is limited due to the shortage of systematic evolutionary studies. Therefore, the three central questions we address are: Do bacteria resistant to multiple antibiotics become hypersensitive to certain antimicrobial peptides? What are the evolutionary mechanisms leading to AMP resistance and to what extent does this process induce cross-resistance/collateral sensitivity against other drugs? Last, are these evolutionary trade-offs predictable based on chemical and functional peptide properties? To investigate these issues rigorously, we integrate tools of laboratory evolution, high-throughput phenotypic assays, functional genomics, and computational systems biology. Our project will provide an insight into the evolutionary mechanisms that drive cross-resistance and collateral sensitivities with the aim to explore the vulnerable points of resistant bacteria. Another goal is to provide guidelines for the future design of antimicrobial peptides with desirable properties against bacterial pathogens.
Summary
Evolution of resistance towards a single drug simultaneously increases (cross-resistance) or decreases (collateral sensitivity) fitness to multiple other antimicrobial agents. The molecular mechanisms driving cross-resistance are relatively well described, but it remains largely unclear how frequently does genetic adaptation to a single drug increase the sensitivity to others and what the underlying molecular mechanisms of collateral sensitivity are. This proposal focuses on studying the bacterial evolution of resistance and collateral sensitivity against antimicrobial peptides (AMPs). Beyond their modulatory roles in the immune system, these naturally occurring peptides provide protection against pathogenic microbes, and are considered as promising novel alternatives to traditional antibiotics. However, there are concerns that evolution against therapeutic AMPs can readily develop and as a by-product this might compromise natural immunity. Our knowledge of these issues is limited due to the shortage of systematic evolutionary studies. Therefore, the three central questions we address are: Do bacteria resistant to multiple antibiotics become hypersensitive to certain antimicrobial peptides? What are the evolutionary mechanisms leading to AMP resistance and to what extent does this process induce cross-resistance/collateral sensitivity against other drugs? Last, are these evolutionary trade-offs predictable based on chemical and functional peptide properties? To investigate these issues rigorously, we integrate tools of laboratory evolution, high-throughput phenotypic assays, functional genomics, and computational systems biology. Our project will provide an insight into the evolutionary mechanisms that drive cross-resistance and collateral sensitivities with the aim to explore the vulnerable points of resistant bacteria. Another goal is to provide guidelines for the future design of antimicrobial peptides with desirable properties against bacterial pathogens.
Max ERC Funding
1 846 250 €
Duration
Start date: 2015-10-01, End date: 2021-09-30
