Project acronym Amitochondriates
Project Life without mitochondrion
Researcher (PI) Vladimir HAMPL
Host Institution (HI) UNIVERZITA KARLOVA
Call Details Consolidator Grant (CoG), LS8, ERC-2017-COG
Summary Mitochondria are often referred to as the “power houses” of eukaryotic cells. All eukaryotes were thought to have mitochondria of some form until 2016, when the first eukaryote thriving without mitochondria was discovered by our laboratory – a flagellate Monocercomonoides. Understanding cellular functions of these cells, which represent a new functional type of eukaryotes, and understanding the circumstances of the unique event of mitochondrial loss are motivations for this proposal. The first objective focuses on the cell physiology. We will perform a metabolomic study revealing major metabolic pathways and concentrate further on elucidating its unique system of iron-sulphur cluster assembly. In the second objective, we will investigate in details the unique case of mitochondrial loss. We will examine two additional potentially amitochondriate lineages by means of genomics and transcriptomics, conduct experiments simulating the moments of mitochondrial loss and try to induce the mitochondrial loss in vitro by knocking out or down genes for mitochondrial biogenesis. We have chosen Giardia intestinalis and Entamoeba histolytica as models for the latter experiments, because their mitochondria are already reduced to minimalistic “mitosomes” and because some genetic tools are already available for them. Successful mitochondrial knock-outs would enable us to study mitochondrial loss in ‘real time’ and in vivo. In the third objective, we will focus on transforming Monocercomonoides into a tractable laboratory model by developing methods of axenic cultivation and genetic manipulation. This will open new possibilities in the studies of this organism and create a cell culture representing an amitochondriate model for cell biological studies enabling the dissection of mitochondrial effects from those of other compartments. The team is composed of the laboratory of PI and eight invited experts and we hope it has the ability to address these challenging questions.
Summary
Mitochondria are often referred to as the “power houses” of eukaryotic cells. All eukaryotes were thought to have mitochondria of some form until 2016, when the first eukaryote thriving without mitochondria was discovered by our laboratory – a flagellate Monocercomonoides. Understanding cellular functions of these cells, which represent a new functional type of eukaryotes, and understanding the circumstances of the unique event of mitochondrial loss are motivations for this proposal. The first objective focuses on the cell physiology. We will perform a metabolomic study revealing major metabolic pathways and concentrate further on elucidating its unique system of iron-sulphur cluster assembly. In the second objective, we will investigate in details the unique case of mitochondrial loss. We will examine two additional potentially amitochondriate lineages by means of genomics and transcriptomics, conduct experiments simulating the moments of mitochondrial loss and try to induce the mitochondrial loss in vitro by knocking out or down genes for mitochondrial biogenesis. We have chosen Giardia intestinalis and Entamoeba histolytica as models for the latter experiments, because their mitochondria are already reduced to minimalistic “mitosomes” and because some genetic tools are already available for them. Successful mitochondrial knock-outs would enable us to study mitochondrial loss in ‘real time’ and in vivo. In the third objective, we will focus on transforming Monocercomonoides into a tractable laboratory model by developing methods of axenic cultivation and genetic manipulation. This will open new possibilities in the studies of this organism and create a cell culture representing an amitochondriate model for cell biological studies enabling the dissection of mitochondrial effects from those of other compartments. The team is composed of the laboratory of PI and eight invited experts and we hope it has the ability to address these challenging questions.
Max ERC Funding
1 935 500 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym BABE
Project Why is the world green: testing top-down control of plant-herbivore food webs by experiments with birds, bats and ants
Researcher (PI) Katerina SAM
Host Institution (HI) Biologicke centrum AV CR, v. v. i.
Call Details Starting Grant (StG), LS8, ERC-2018-STG
Summary Why is the world green? Because predators control herbivores, allowing plants to flourish. This >50 years old answer to the deceptively simple question remains controversial. After all, plants are also protected from herbivores physically and by secondary chemistry. My goal is to test novel aspects of the “green world hypothesis”: ● How the importance of top-down effects varies with forest diversity and productivity along a latitudinal gradient? ● How the key predators, birds, bats and ants, contribute to top-down effects individually and in synergy? I strive to understand this because: ● While there is evidence that predators reduce herbivore abundance and enhance plant growth, the importance of top-down control is poorly understood across a range of forests. ● The importance of key predatory groups, and their antagonistic and synergic interactions, have been rarely studied, despite their potential impact on ecosystem dynamics in changing world. I wish to achieve my goals by: ● Factorial manipulations of key insectivorous predators (birds, bats, ants) to measure their effects on lower trophic levels in forest understories and canopies, accessed by canopy cranes, along latitudinal gradient spanning 75o from Australia to Japan. ● Studying compensatory effects among predatory taxa on herbivore and plant performance. Why this has not been done before: ● Factorial experimental exclusion of predatory groups replicated on a large spatial scale is logistically difficult. ● Canopy crane network along a latitudinal gradient has only recently become available. I am in excellent position to succeed as I have experience with ● foodweb experiments along an elevation gradient in New Guinea rainforests, ● study of bird, bat and arthropod communities. If the project is successful, it will: ● Allow understanding the importance of predators from temperate to tropical forests. ● Establish a network of experimental sites along a network of canopy cranes open for follow-up research.
Summary
Why is the world green? Because predators control herbivores, allowing plants to flourish. This >50 years old answer to the deceptively simple question remains controversial. After all, plants are also protected from herbivores physically and by secondary chemistry. My goal is to test novel aspects of the “green world hypothesis”: ● How the importance of top-down effects varies with forest diversity and productivity along a latitudinal gradient? ● How the key predators, birds, bats and ants, contribute to top-down effects individually and in synergy? I strive to understand this because: ● While there is evidence that predators reduce herbivore abundance and enhance plant growth, the importance of top-down control is poorly understood across a range of forests. ● The importance of key predatory groups, and their antagonistic and synergic interactions, have been rarely studied, despite their potential impact on ecosystem dynamics in changing world. I wish to achieve my goals by: ● Factorial manipulations of key insectivorous predators (birds, bats, ants) to measure their effects on lower trophic levels in forest understories and canopies, accessed by canopy cranes, along latitudinal gradient spanning 75o from Australia to Japan. ● Studying compensatory effects among predatory taxa on herbivore and plant performance. Why this has not been done before: ● Factorial experimental exclusion of predatory groups replicated on a large spatial scale is logistically difficult. ● Canopy crane network along a latitudinal gradient has only recently become available. I am in excellent position to succeed as I have experience with ● foodweb experiments along an elevation gradient in New Guinea rainforests, ● study of bird, bat and arthropod communities. If the project is successful, it will: ● Allow understanding the importance of predators from temperate to tropical forests. ● Establish a network of experimental sites along a network of canopy cranes open for follow-up research.
Max ERC Funding
1 455 032 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
Project acronym BEHAVFRICTIONS
Project Behavioral Implications of Information-Processing Frictions
Researcher (PI) Jakub STEINER
Host Institution (HI) NARODOHOSPODARSKY USTAV AKADEMIE VED CESKE REPUBLIKY VEREJNA VYZKUMNA INSTITUCE
Call Details Consolidator Grant (CoG), SH1, ERC-2017-COG
Summary BEHAVFRICTIONS will use novel models focussing on information-processing frictions to explain choice patterns described in behavioral economics and psychology. The proposed research will provide microfoundations that are essential for (i) identification of stable preferences, (ii) counterfactual predictions, and (iii) normative conclusions.
(i) Agents who face information-processing costs must trade the precision of choice against information costs. Their behavior thus reflects both their stable preferences and the context-dependent procedures that manage their errors stemming from imperfect information processing. In the absence of micro-founded models, the two drivers of the behavior are difficult to disentangle for outside observers. In some pillars of the proposal, the agents follow choice rules that closely resemble logit rules used in structural estimation. This will allow me to reinterpret the structural estimation fits to choice data and to make a distinction between the stable preferences and frictions.
(ii) Such a distinction is important in counterfactual policy analysis because the second-best decision procedures that manage the errors in choice are affected by the analysed policy. Incorporation of the information-processing frictions into existing empirical methods will improve our ability to predict effects of the policies.
(iii) My preliminary results suggest that when an agent is prone to committing errors, biases--such as overconfidence, confirmatory bias, or perception biases known from prospect theory--arise under second-best strategies. By providing the link between the agent's environment and the second-best distribution of the perception errors, my models will delineate environments in which these biases shield the agents from the most costly mistakes from environments in which the biases turn into maladaptations. The distinction will inform the normative debate on debiasing.
Summary
BEHAVFRICTIONS will use novel models focussing on information-processing frictions to explain choice patterns described in behavioral economics and psychology. The proposed research will provide microfoundations that are essential for (i) identification of stable preferences, (ii) counterfactual predictions, and (iii) normative conclusions.
(i) Agents who face information-processing costs must trade the precision of choice against information costs. Their behavior thus reflects both their stable preferences and the context-dependent procedures that manage their errors stemming from imperfect information processing. In the absence of micro-founded models, the two drivers of the behavior are difficult to disentangle for outside observers. In some pillars of the proposal, the agents follow choice rules that closely resemble logit rules used in structural estimation. This will allow me to reinterpret the structural estimation fits to choice data and to make a distinction between the stable preferences and frictions.
(ii) Such a distinction is important in counterfactual policy analysis because the second-best decision procedures that manage the errors in choice are affected by the analysed policy. Incorporation of the information-processing frictions into existing empirical methods will improve our ability to predict effects of the policies.
(iii) My preliminary results suggest that when an agent is prone to committing errors, biases--such as overconfidence, confirmatory bias, or perception biases known from prospect theory--arise under second-best strategies. By providing the link between the agent's environment and the second-best distribution of the perception errors, my models will delineate environments in which these biases shield the agents from the most costly mistakes from environments in which the biases turn into maladaptations. The distinction will inform the normative debate on debiasing.
Max ERC Funding
1 321 488 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym CELLONGATE
Project Unraveling the molecular network that drives cell growth in plants
Researcher (PI) Matyas FENDRYCH
Host Institution (HI) UNIVERZITA KARLOVA
Call Details Starting Grant (StG), LS3, ERC-2018-STG
Summary Plants differ strikingly from animals by the almost total absence of cell migration in their development. Plants build their bodies using a hydrostatic skeleton that consists of pressurized cells encased by a cell wall. Consequently, plant cells cannot migrate and must sculpture their bodies by orientation of cell division and precise regulation of cell growth. Cell growth depends on the balance between internal cell pressure – turgor, and strength of the cell wall. Cell growth is under a strict developmental control, which is exemplified in the Arabidopsis thaliana root tip, where massive cell elongation occurs in a defined spatio-temporal developmental window. Despite the immobility of their cells, plant organs move to optimize light and nutrient acquisition and to orient their bodies along the gravity vector. These movements depend on differential regulation of cell elongation across the organ, and on response to the phytohormone auxin. Even though the control of cell growth is in the epicenter of plant development, protein networks steering the developmental growth onset, coordination and termination remain elusive. Similarly, although auxin is the central regulator of growth, the molecular mechanism of its effect on root growth is unknown. In this project, I will establish a unique microscopy setup for high spatio-temporal resolution live-cell imaging equipped with a microfluidic lab-on-chip platform optimized for growing roots, to enable analysis and manipulation of root growth physiology. I will use developmental gradients in the root to discover genes that steer cellular growth, by correlating transcriptome profiles of individual cell types with the cell size. In parallel, I will exploit the auxin effect on root to unravel molecular mechanisms that control cell elongation. Finally, I am going to combine the live-cell imaging methodology with the gene discovery approaches to chart a dynamic spatio-temporal physiological map of a growing Arabidopsis root.
Summary
Plants differ strikingly from animals by the almost total absence of cell migration in their development. Plants build their bodies using a hydrostatic skeleton that consists of pressurized cells encased by a cell wall. Consequently, plant cells cannot migrate and must sculpture their bodies by orientation of cell division and precise regulation of cell growth. Cell growth depends on the balance between internal cell pressure – turgor, and strength of the cell wall. Cell growth is under a strict developmental control, which is exemplified in the Arabidopsis thaliana root tip, where massive cell elongation occurs in a defined spatio-temporal developmental window. Despite the immobility of their cells, plant organs move to optimize light and nutrient acquisition and to orient their bodies along the gravity vector. These movements depend on differential regulation of cell elongation across the organ, and on response to the phytohormone auxin. Even though the control of cell growth is in the epicenter of plant development, protein networks steering the developmental growth onset, coordination and termination remain elusive. Similarly, although auxin is the central regulator of growth, the molecular mechanism of its effect on root growth is unknown. In this project, I will establish a unique microscopy setup for high spatio-temporal resolution live-cell imaging equipped with a microfluidic lab-on-chip platform optimized for growing roots, to enable analysis and manipulation of root growth physiology. I will use developmental gradients in the root to discover genes that steer cellular growth, by correlating transcriptome profiles of individual cell types with the cell size. In parallel, I will exploit the auxin effect on root to unravel molecular mechanisms that control cell elongation. Finally, I am going to combine the live-cell imaging methodology with the gene discovery approaches to chart a dynamic spatio-temporal physiological map of a growing Arabidopsis root.
Max ERC Funding
1 498 750 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym CRAACE
Project Continuity and Rupture in Central European Art and Architecture, 1918-1939
Researcher (PI) Matthew RAMPLEY
Host Institution (HI) Masarykova univerzita
Call Details Advanced Grant (AdG), SH5, ERC-2017-ADG
Summary When new political elites and social structures emerge out of a historical rupture, how are art and architecture affected? In 1918 the political map of central Europe was redrawn as a result of the collapse of Austria-Hungary, marking a new era for the region. Through comparative analysis of the visual arts in 3 states built on the ruins of the Habsburg Empire (Austria, Hungary and [former] Czechoslovakia), this project examines how such political discontinuity affected art and architecture between 1918 and 1939. The project is organised into 4 themes, each resulting in a monograph:
1. Vernacular modernisms, nostalgia and the avant-garde
2. Presenting the state: world fairs and exhibitionary cultures
3. Piety, reaction and renewal
4. Contested histories: monuments, memory and representations of the historical past
It is the first systematic and comprehensive trans-national study of this type, based on the claim that the successor states to Austria-Hungary belonged to a common cultural space informed by the shared memory of the long years of Habsburg society and culture. The project focuses on the contradictory ways that visual arts of artists and architects in central Europe adapted to and tried to shape new socio-political circumstances in the light of the past. The project thus examines the long shadow of the Habsburg Empire over the art and culture of the twentieth century.
The project also considers the impact of the political and ideological imperatives of the three successor states on the visual arts; how did governments treat the past? Did they encourage a sense of historical caesura or look to the past for legitimation? How did artists and architects respond to such new impulses? In answering these questions the project analyses the conflicts between avant-gardes and more conservative artistic movements; the role of the visual arts in interwar memory politics; the place of art in the nexus of religion, national and state identity.
Summary
When new political elites and social structures emerge out of a historical rupture, how are art and architecture affected? In 1918 the political map of central Europe was redrawn as a result of the collapse of Austria-Hungary, marking a new era for the region. Through comparative analysis of the visual arts in 3 states built on the ruins of the Habsburg Empire (Austria, Hungary and [former] Czechoslovakia), this project examines how such political discontinuity affected art and architecture between 1918 and 1939. The project is organised into 4 themes, each resulting in a monograph:
1. Vernacular modernisms, nostalgia and the avant-garde
2. Presenting the state: world fairs and exhibitionary cultures
3. Piety, reaction and renewal
4. Contested histories: monuments, memory and representations of the historical past
It is the first systematic and comprehensive trans-national study of this type, based on the claim that the successor states to Austria-Hungary belonged to a common cultural space informed by the shared memory of the long years of Habsburg society and culture. The project focuses on the contradictory ways that visual arts of artists and architects in central Europe adapted to and tried to shape new socio-political circumstances in the light of the past. The project thus examines the long shadow of the Habsburg Empire over the art and culture of the twentieth century.
The project also considers the impact of the political and ideological imperatives of the three successor states on the visual arts; how did governments treat the past? Did they encourage a sense of historical caesura or look to the past for legitimation? How did artists and architects respond to such new impulses? In answering these questions the project analyses the conflicts between avant-gardes and more conservative artistic movements; the role of the visual arts in interwar memory politics; the place of art in the nexus of religion, national and state identity.
Max ERC Funding
2 468 359 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym CRISP
Project Cognitive Aging: From Educational Opportunities to Individual Risk Profiles
Researcher (PI) Anja LEIST
Host Institution (HI) UNIVERSITE DU LUXEMBOURG
Call Details Starting Grant (StG), SH3, ERC-2018-STG
Summary Cognitive impairment and dementia have dramatic individual and social consequences, and create high economic costs for societies. In order to delay cognitive aging of future generations as long as possible, we need evidence about which contextual factors are most supportive for individuals to reach highest cognitive levels relative to their potential. At the same time, for current older generations, we need scalable methods to exactly identify individuals at risk of cognitive impairment. The project intends to apply recent methodological and statistical advancements to reach two objectives. Firstly, contextual influences on cognitive aging will be comparatively assessed, with a focus on inequalities related to educational opportunities and gender inequalities. This will be done using longitudinal, population-representative, harmonized cross-national aging surveys, merged with contextual information. Secondly, the project will quantify the ability of singular and clustered individual characteristics, such as indicators of cognitive reserve and behaviour change, to predict cognitive aging and diagnosis of dementia. Project methodology will rely partly on parametric ‘traditional’ multilevel- or fixed-effects modelling, partly on non-parametric statistical learning approaches, to address objectives both hypothesis- and data-driven. Applying statistical learning techniques in the field of cognitive reserve will open new research avenues for efficient handling of large amounts of data, among which most prominently the accurate prediction of health and disease outcomes. Quantifying the role of contextual inequalities related to education and gender will guide policymaking in and beyond the project. Assessing risk profiles of individuals in relation to cognitive aging will support efficient and scalable risk screening of individuals. Identifying the value of behaviour change to delay cognitive impairment will guide treatment plans for individuals affected by dementia.
Summary
Cognitive impairment and dementia have dramatic individual and social consequences, and create high economic costs for societies. In order to delay cognitive aging of future generations as long as possible, we need evidence about which contextual factors are most supportive for individuals to reach highest cognitive levels relative to their potential. At the same time, for current older generations, we need scalable methods to exactly identify individuals at risk of cognitive impairment. The project intends to apply recent methodological and statistical advancements to reach two objectives. Firstly, contextual influences on cognitive aging will be comparatively assessed, with a focus on inequalities related to educational opportunities and gender inequalities. This will be done using longitudinal, population-representative, harmonized cross-national aging surveys, merged with contextual information. Secondly, the project will quantify the ability of singular and clustered individual characteristics, such as indicators of cognitive reserve and behaviour change, to predict cognitive aging and diagnosis of dementia. Project methodology will rely partly on parametric ‘traditional’ multilevel- or fixed-effects modelling, partly on non-parametric statistical learning approaches, to address objectives both hypothesis- and data-driven. Applying statistical learning techniques in the field of cognitive reserve will open new research avenues for efficient handling of large amounts of data, among which most prominently the accurate prediction of health and disease outcomes. Quantifying the role of contextual inequalities related to education and gender will guide policymaking in and beyond the project. Assessing risk profiles of individuals in relation to cognitive aging will support efficient and scalable risk screening of individuals. Identifying the value of behaviour change to delay cognitive impairment will guide treatment plans for individuals affected by dementia.
Max ERC Funding
1 148 290 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym FunDiT
Project Functional Diversity of T cells
Researcher (PI) Ondrej STEPANEK
Host Institution (HI) USTAV MOLEKULARNI GENETIKY AKADEMIE VED CESKE REPUBLIKY VEREJNA VYZKUMNA INSTITUCE
Call Details Starting Grant (StG), LS6, ERC-2018-STG
Summary T cells have a central role in most adaptive immune responses, including immunity to infection, cancer, and autoimmunity. Increasing evidence shows that even resting steady-state T cells form many different subsets with unique functions. Variable level of self-reactivity and previous antigenic exposure are most likely two major determinants of the T-cell diversity. However, the number, identity, and biological function of steady-state T-cell subsets are still very incompletely understood. Receptors to ligands from TNF and B7 families exhibit variable expression among T-cell subsets and are important regulators of T-cell fate decisions. We hypothesize that pathways triggered by these receptors substantially contribute to the functional diversity of T cells.The FunDiT project uses a set of novel tools to systematically identify steady-state CD8+ T cell subsets and characterize their biological roles. The project has three complementary objectives.
(1) Identification of CD8+ T cell subsets. We will identify subsets based on single cell gene expression profiling. We will determine the role of self and foreign antigens in the formation of these subsets and match corresponding subsets between mice and humans.
(2) Role of particular subsets in the immune response. We will compare antigenic responses of particular subsets using our novel model allowing inducible expression of a defined TCR. The activity of T-cell subsets in three disease models (infection, cancer, autoimmunity) will be characterized.
(3) Characterization of key costimulatory/inhibitory pathways. We will use our novel mass spectrometry-based approach to identify receptors and signaling molecules involved in the signaling by ligands from TNF and B7 families in T cells.
The results will provide understanding of the adaptive immunity in particular disease context and resolve long-standing questions concerning the roles of T-cell diversity in protective immunity and tolerance to healthy tissues and tumors.
Summary
T cells have a central role in most adaptive immune responses, including immunity to infection, cancer, and autoimmunity. Increasing evidence shows that even resting steady-state T cells form many different subsets with unique functions. Variable level of self-reactivity and previous antigenic exposure are most likely two major determinants of the T-cell diversity. However, the number, identity, and biological function of steady-state T-cell subsets are still very incompletely understood. Receptors to ligands from TNF and B7 families exhibit variable expression among T-cell subsets and are important regulators of T-cell fate decisions. We hypothesize that pathways triggered by these receptors substantially contribute to the functional diversity of T cells.The FunDiT project uses a set of novel tools to systematically identify steady-state CD8+ T cell subsets and characterize their biological roles. The project has three complementary objectives.
(1) Identification of CD8+ T cell subsets. We will identify subsets based on single cell gene expression profiling. We will determine the role of self and foreign antigens in the formation of these subsets and match corresponding subsets between mice and humans.
(2) Role of particular subsets in the immune response. We will compare antigenic responses of particular subsets using our novel model allowing inducible expression of a defined TCR. The activity of T-cell subsets in three disease models (infection, cancer, autoimmunity) will be characterized.
(3) Characterization of key costimulatory/inhibitory pathways. We will use our novel mass spectrometry-based approach to identify receptors and signaling molecules involved in the signaling by ligands from TNF and B7 families in T cells.
The results will provide understanding of the adaptive immunity in particular disease context and resolve long-standing questions concerning the roles of T-cell diversity in protective immunity and tolerance to healthy tissues and tumors.
Max ERC Funding
1 725 000 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym LeukemiaEnviron
Project SIGNALING PROPENSITY IN THE MICROENVIRONMENT OF B CELL CHRONIC LYMPHOCYTIC LEUKEMIA
Researcher (PI) Marek Mraz
Host Institution (HI) Masarykova univerzita
Call Details Starting Grant (StG), LS4, ERC-2018-STG
Summary B cell chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults. CLL cells are characterized by their universal dependency on pro-survival and pro-proliferative signals from immune niches. To achieve this they constantly re-circulate between blood and lymph nodes, which is inhibited by novel microenvironment-targeting therapies such as “BCR inhibitors”. We aim to reveal how the malignant B cells change the propensity of their signalling pathways in response to the different microenvironments such as peripheral blood vs lymph node to obtain the proliferative signals. This is of major relevance for CLL, but also transferable to the biology of some other B cell malignancies and/or normal B cells. We analyzed the “finger print” of microenvironmental interactions in many CLL samples at various times during the disease course or during therapy. The obtained data led us to hypothesize on the mechanisms of regulation of signalling propensity of two pathways that are responsible for proliferation and survival of CLL cells, namely B Cell Receptor (BCR) signalling and signals from T-cells mediated by CD40/IL4. In aim 1 we hypothesize that CD20 is one of the key proteins involved in CLL cell activation, and influences BCR and interleukin signalling (see figure). This has important therapeutic implication since CD20 is used as a therapeutic target for 20 years (rituximab), but its function in CLL/normal B cells is unknown. In aim 2 we hypothesize that miR-29 acts a key regulator of T-cell signalling from CD40 and down-stream NFkB activation (see figure). This represents the first example of miRNAs‘ role in the propensity of T-cell interaction, and could be also utilized therapeutically. In aim 3 we will integrate our data on microenvironmental signaling (aim 1+2) and develop a first mouse model for PDX that would allow stable engraftment of primary CLL cells. Currently, CLL is non-transplantable to any animal model which complicates studies of its biology.
Summary
B cell chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults. CLL cells are characterized by their universal dependency on pro-survival and pro-proliferative signals from immune niches. To achieve this they constantly re-circulate between blood and lymph nodes, which is inhibited by novel microenvironment-targeting therapies such as “BCR inhibitors”. We aim to reveal how the malignant B cells change the propensity of their signalling pathways in response to the different microenvironments such as peripheral blood vs lymph node to obtain the proliferative signals. This is of major relevance for CLL, but also transferable to the biology of some other B cell malignancies and/or normal B cells. We analyzed the “finger print” of microenvironmental interactions in many CLL samples at various times during the disease course or during therapy. The obtained data led us to hypothesize on the mechanisms of regulation of signalling propensity of two pathways that are responsible for proliferation and survival of CLL cells, namely B Cell Receptor (BCR) signalling and signals from T-cells mediated by CD40/IL4. In aim 1 we hypothesize that CD20 is one of the key proteins involved in CLL cell activation, and influences BCR and interleukin signalling (see figure). This has important therapeutic implication since CD20 is used as a therapeutic target for 20 years (rituximab), but its function in CLL/normal B cells is unknown. In aim 2 we hypothesize that miR-29 acts a key regulator of T-cell signalling from CD40 and down-stream NFkB activation (see figure). This represents the first example of miRNAs‘ role in the propensity of T-cell interaction, and could be also utilized therapeutically. In aim 3 we will integrate our data on microenvironmental signaling (aim 1+2) and develop a first mouse model for PDX that would allow stable engraftment of primary CLL cells. Currently, CLL is non-transplantable to any animal model which complicates studies of its biology.
Max ERC Funding
1 499 990 €
Duration
Start date: 2019-06-01, End date: 2024-05-31
Project acronym ToMeTuM
Project Towards the Understanding a Metal-Tumour-Metabolism
Researcher (PI) Vojtech Adam
Host Institution (HI) VYSOKE UCENI TECHNICKE V BRNE
Call Details Starting Grant (StG), LS7, ERC-2017-STG
Summary A tumour cell uses both genetic and protein weapons in its development. Gaining a greater understanding of these lethal mechanisms is a key step towards developing novel and more effective treatments. Because the metal ion metabolism of a tumour cell is not fully understood, we will address the challenge of explaining the mechanisms of how a tumour cell copes both with essential metal ions and platinum based drugs. The metal-based mechanisms help a tumour to grow on one side and to protect itself against commonly used metal-based drugs. On the other side, the exact description of these mechanisms, which are being associated with multi-drug resistance occurrence and failure of a treatment, still remains unclear. We will reveal the mechanism of the as yet not understood biochemical and molecularly-biological relationships and correlations between metal ions and proteins in a tumour development revealing the way how to suppress the growth and development of a tumour and to markedly enhance the effectiveness of a treatment.
To achieve this goal, we will focus on metallothionein and its interactions with essential metals and metal-containing anticancer drugs (cisplatin, carboplatin, and oxaliplatin). Their actions will be monitored both in vitro and in vivo. For this purpose, we will optimize electrochemical, mass spectrometric and immune-based methods. Based on processing of data obtained, new carcinogenetic pathways will be sought on cell level and proved by genetic modifications of target genes. The discovered processes and the pathways found will then be tested on two animal experimental models mice bearing breast tumours (MCF-7 and 4T1) and MeLiM minipigs bearing melanomas.
The precise description of the tumour related pathways coping with metal ions based on metallothioneins will direct new highly effective treatment strategies. Moreover, the discovery of new carcinogenetic pathways will open a window for understanding of cancer formation and development.
Summary
A tumour cell uses both genetic and protein weapons in its development. Gaining a greater understanding of these lethal mechanisms is a key step towards developing novel and more effective treatments. Because the metal ion metabolism of a tumour cell is not fully understood, we will address the challenge of explaining the mechanisms of how a tumour cell copes both with essential metal ions and platinum based drugs. The metal-based mechanisms help a tumour to grow on one side and to protect itself against commonly used metal-based drugs. On the other side, the exact description of these mechanisms, which are being associated with multi-drug resistance occurrence and failure of a treatment, still remains unclear. We will reveal the mechanism of the as yet not understood biochemical and molecularly-biological relationships and correlations between metal ions and proteins in a tumour development revealing the way how to suppress the growth and development of a tumour and to markedly enhance the effectiveness of a treatment.
To achieve this goal, we will focus on metallothionein and its interactions with essential metals and metal-containing anticancer drugs (cisplatin, carboplatin, and oxaliplatin). Their actions will be monitored both in vitro and in vivo. For this purpose, we will optimize electrochemical, mass spectrometric and immune-based methods. Based on processing of data obtained, new carcinogenetic pathways will be sought on cell level and proved by genetic modifications of target genes. The discovered processes and the pathways found will then be tested on two animal experimental models mice bearing breast tumours (MCF-7 and 4T1) and MeLiM minipigs bearing melanomas.
The precise description of the tumour related pathways coping with metal ions based on metallothioneins will direct new highly effective treatment strategies. Moreover, the discovery of new carcinogenetic pathways will open a window for understanding of cancer formation and development.
Max ERC Funding
1 377 495 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym UnRef
Project Unlikely refuge? Refugees and citizens in East-Central Europe in the 20th century
Researcher (PI) Michal FRANKL
Host Institution (HI) MASARYKUV USTAV A ARCHIV AV CR VVI
Call Details Consolidator Grant (CoG), SH6, ERC-2018-COG
Summary The project aims to write refugees back into the history of East-Central Europe in the 20th century. In this “age of refugees”, the region became a destination of large refugee migrations, forcing civil societies and governments to negotiate difficult decisions about protection for those fleeing the war and persecution. Yet, at the same time, East-Central Europe does not enjoy the reputation as a welcoming place for people persecuted for political persuasion, for their “racial”, ethnic identity or any other reason. It would appear that the histories of ethnic conflict and violence, political oppression and economic underdevelopment make it a place to leave behind rather than to search for as a safe harbour.
Studies about specific groups and instances notwithstanding, historical research remains highly unsatisfactory, failing to address refugee protection in a systematic comparative way and transcending national master narratives. Worse than this, historical writing about refugees in the “East” often re-inscribes the very (ethnic, political) categories which lead to the production of refugees in the first place.
Comparative research spanning across a longer period and a wider territory promises therefore not only major insights about the “East” as a refuge, but also a significant contribution to the emerging field of global refugee history. In this project, an international research team led by the PI will, using comparative historical research combined with multi-disciplinary approaches, probe the multifaceted entanglements with refugees in countries created in 1918 on the ruins of the Habsburg Monarchy (Poland, Czechoslovakia, Austria, Hungary, Yugoslavia) over the 20th century. By doing so, it wishes to return the discussion of protection of refugees into the region’s history and to contribute – from a scholarly perspective – to the cultivation of current and future public debate about this divisive subject.
Summary
The project aims to write refugees back into the history of East-Central Europe in the 20th century. In this “age of refugees”, the region became a destination of large refugee migrations, forcing civil societies and governments to negotiate difficult decisions about protection for those fleeing the war and persecution. Yet, at the same time, East-Central Europe does not enjoy the reputation as a welcoming place for people persecuted for political persuasion, for their “racial”, ethnic identity or any other reason. It would appear that the histories of ethnic conflict and violence, political oppression and economic underdevelopment make it a place to leave behind rather than to search for as a safe harbour.
Studies about specific groups and instances notwithstanding, historical research remains highly unsatisfactory, failing to address refugee protection in a systematic comparative way and transcending national master narratives. Worse than this, historical writing about refugees in the “East” often re-inscribes the very (ethnic, political) categories which lead to the production of refugees in the first place.
Comparative research spanning across a longer period and a wider territory promises therefore not only major insights about the “East” as a refuge, but also a significant contribution to the emerging field of global refugee history. In this project, an international research team led by the PI will, using comparative historical research combined with multi-disciplinary approaches, probe the multifaceted entanglements with refugees in countries created in 1918 on the ruins of the Habsburg Monarchy (Poland, Czechoslovakia, Austria, Hungary, Yugoslavia) over the 20th century. By doing so, it wishes to return the discussion of protection of refugees into the region’s history and to contribute – from a scholarly perspective – to the cultivation of current and future public debate about this divisive subject.
Max ERC Funding
1 995 950 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
