Project acronym ADHESWITCHES
Project Adhesion switches in cancer and development: from in vivo to synthetic biology
Researcher (PI) Mari Johanna Ivaska
Host Institution (HI) TURUN YLIOPISTO
Country Finland
Call Details Consolidator Grant (CoG), LS3, ERC-2013-CoG
Summary Integrins are transmembrane cell adhesion receptors controlling cell proliferation and migration. Our objective is to gain fundamentally novel mechanistic insight into the emerging new roles of integrins in cancer and to generate a road map of integrin dependent pathways critical in mammary gland development and integrin signalling thus opening new targets for therapeutic interventions. We will combine an in vivo based translational approach with cell and molecular biological studies aiming to identify entirely novel concepts in integrin function using cutting edge techniques and synthetic-biology tools.
The specific objectives are:
1) Integrin inactivation in branching morphogenesis and cancer invasion. Integrins regulate mammary gland development and cancer invasion but the role of integrin inactivating proteins in these processes is currently completely unknown. We will investigate this using genetically modified mice, ex-vivo organoid models and human tissues with the aim to identify beneficial combinational treatments against cancer invasion.
2) Endosomal adhesomes – cross-talk between integrin activity and integrin “inside-in signaling”. We hypothesize that endocytosed active integrins engage in specialized endosomal signaling that governs cell survival especially in cancer. RNAi cell arrays, super-resolution STED imaging and endosomal proteomics will be used to investigate integrin signaling in endosomes.
3) Spatio-temporal co-ordination of adhesion and endocytosis. Several cytosolic proteins compete for integrin binding to regulate activation, endocytosis and recycling. Photoactivatable protein-traps and predefined matrix micropatterns will be employed to mechanistically dissect the spatio-temporal dynamics and hierarchy of their recruitment.
We will employ innovative and unconventional techniques to address three major unanswered questions in the field and significantly advance our understanding of integrin function in development and cancer.
Summary
Integrins are transmembrane cell adhesion receptors controlling cell proliferation and migration. Our objective is to gain fundamentally novel mechanistic insight into the emerging new roles of integrins in cancer and to generate a road map of integrin dependent pathways critical in mammary gland development and integrin signalling thus opening new targets for therapeutic interventions. We will combine an in vivo based translational approach with cell and molecular biological studies aiming to identify entirely novel concepts in integrin function using cutting edge techniques and synthetic-biology tools.
The specific objectives are:
1) Integrin inactivation in branching morphogenesis and cancer invasion. Integrins regulate mammary gland development and cancer invasion but the role of integrin inactivating proteins in these processes is currently completely unknown. We will investigate this using genetically modified mice, ex-vivo organoid models and human tissues with the aim to identify beneficial combinational treatments against cancer invasion.
2) Endosomal adhesomes – cross-talk between integrin activity and integrin “inside-in signaling”. We hypothesize that endocytosed active integrins engage in specialized endosomal signaling that governs cell survival especially in cancer. RNAi cell arrays, super-resolution STED imaging and endosomal proteomics will be used to investigate integrin signaling in endosomes.
3) Spatio-temporal co-ordination of adhesion and endocytosis. Several cytosolic proteins compete for integrin binding to regulate activation, endocytosis and recycling. Photoactivatable protein-traps and predefined matrix micropatterns will be employed to mechanistically dissect the spatio-temporal dynamics and hierarchy of their recruitment.
We will employ innovative and unconventional techniques to address three major unanswered questions in the field and significantly advance our understanding of integrin function in development and cancer.
Max ERC Funding
1 887 910 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym ANTILEAK
Project Development of antagonists of vascular leakage
Researcher (PI) Pipsa SAHARINEN
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Consolidator Grant (CoG), LS4, ERC-2017-COG
Summary Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.
Summary
Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.
Max ERC Funding
1 999 770 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym BIZEB
Project Bio-Imaging of Zoonotic and Emerging Bunyaviruses
Researcher (PI) Juha Huiskonen
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Consolidator Grant (CoG), LS1, ERC-2014-CoG
Summary We aim to understand host cell entry of enveloped viruses at molecular level. A crucial step in this process is when the viral membrane fuses with the cell membrane. Similarly to cell–cell fusion, this step is mediated by fusion proteins (classes I–III). Several medically important viruses, notably dengue and many bunyaviruses, harbour a class II fusion protein. Class II fusion protein structures have been solved in pre- and post-fusion conformation and in some cases different factors promoting fusion have been determined. However, questions about the most important steps of this key process remain unanswered. I will focus on the entry mechanism of bunyaviruses by using cutting-edge, high spatial and temporal resolution bio-imaging techniques. These viruses have been chosen as a model system to maximise the significance of the project: they form an emerging viral threat to humans and animals, no approved vaccines or antivirals exist for human use and they are less studied than other class II fusion protein systems. Cryo-electron microscopy and tomography will be used to solve high-resolution structures (up to ~3 Å) of viruses, in addition to virus–receptor and virus–membrane complexes. Advanced fluorescence microscopy techniques will be used to probe the dynamics of virus entry and fusion in vivo and in vitro. Deciphering key steps in virus entry is expected to contribute to rational vaccine and drug design. During this project I aim to establish a world-class laboratory in structural and cellular biology of emerging viruses. The project greatly benefits from our unique biosafety level 3 laboratory offering advanced bio-imaging techniques. Furthermore it will also pave way for similar projects on other infectious viruses. Finally the novel computational image processing methods developed in this project will be broadly applicable for the analysis of flexible biological structures, which often pose the most challenging yet interesting questions in structural biology.
Summary
We aim to understand host cell entry of enveloped viruses at molecular level. A crucial step in this process is when the viral membrane fuses with the cell membrane. Similarly to cell–cell fusion, this step is mediated by fusion proteins (classes I–III). Several medically important viruses, notably dengue and many bunyaviruses, harbour a class II fusion protein. Class II fusion protein structures have been solved in pre- and post-fusion conformation and in some cases different factors promoting fusion have been determined. However, questions about the most important steps of this key process remain unanswered. I will focus on the entry mechanism of bunyaviruses by using cutting-edge, high spatial and temporal resolution bio-imaging techniques. These viruses have been chosen as a model system to maximise the significance of the project: they form an emerging viral threat to humans and animals, no approved vaccines or antivirals exist for human use and they are less studied than other class II fusion protein systems. Cryo-electron microscopy and tomography will be used to solve high-resolution structures (up to ~3 Å) of viruses, in addition to virus–receptor and virus–membrane complexes. Advanced fluorescence microscopy techniques will be used to probe the dynamics of virus entry and fusion in vivo and in vitro. Deciphering key steps in virus entry is expected to contribute to rational vaccine and drug design. During this project I aim to establish a world-class laboratory in structural and cellular biology of emerging viruses. The project greatly benefits from our unique biosafety level 3 laboratory offering advanced bio-imaging techniques. Furthermore it will also pave way for similar projects on other infectious viruses. Finally the novel computational image processing methods developed in this project will be broadly applicable for the analysis of flexible biological structures, which often pose the most challenging yet interesting questions in structural biology.
Max ERC Funding
1 998 375 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym CATCH
Project Cross-dimensional Activation of Two-Dimensional Semiconductors for Photocatalytic Heterojunctions
Researcher (PI) Wei CAO
Host Institution (HI) OULUN YLIOPISTO
Country Finland
Call Details Consolidator Grant (CoG), PE8, ERC-2020-COG
Summary Spacetime defines existence and evolution of materials. A key path to human’s sustainability through materials innovation can hardly circumvent materials dimensionalities. Despite numerous studies in electrically distinct 2D semiconductors, the route to engage them in high-performance photocatalysts remains elusive. Herein, CATCH proposes a cross-dimensional activation strategy of 2D semiconductors to implement practical photocatalysis. It operates electronic structures of dimensionally paradoxical 2D semiconductors and spatially limited nD (n=0-2) guests, directs charge migration processes, mass-produces advanced catalysts and elucidates time-evolved catalysis. Synergic impacts crossing 2D-nD will lead to > 95%/hour rates for pollutant removal and >20% quantum efficiencies for H2 evolution under visible light. CATCH enumerates chemical coordination and writes reaction equations with sub-nanosecond precision.
CATCH employs density functional theory optimization and data mining prediction to select most probable heterojunctional peers from hetero/homo- dimensions. Through facile but efficient wet and dry synthesis, nanostructures will be bonded to basal planes or brinks of 2D slabs. CATCH benefits in-house techniques for product characterizations and refinements and emphasizes on cutting-edge in situ studies to unveil photocatalysis at advanced photon sources. Assisted with theoretical modelling, ambient and time-evolved experiments will illustrate photocatalytic dynamics and kinetics in mixed spacetime.
CATCH unites low-dimensional materials designs by counting physical and electronic merits from spacetime confinements. It metrologically elaborates photocatalysis in an elevated 2D+nD+t, alters passages of materials combinations crossing dimensions, and directs future photocatalyst designs. Standing on cross-dimensional materials innovation and photocatalysis study, CATCH breaks the deadlock of practical photocatalysis that eventually leads to sustainability.
Summary
Spacetime defines existence and evolution of materials. A key path to human’s sustainability through materials innovation can hardly circumvent materials dimensionalities. Despite numerous studies in electrically distinct 2D semiconductors, the route to engage them in high-performance photocatalysts remains elusive. Herein, CATCH proposes a cross-dimensional activation strategy of 2D semiconductors to implement practical photocatalysis. It operates electronic structures of dimensionally paradoxical 2D semiconductors and spatially limited nD (n=0-2) guests, directs charge migration processes, mass-produces advanced catalysts and elucidates time-evolved catalysis. Synergic impacts crossing 2D-nD will lead to > 95%/hour rates for pollutant removal and >20% quantum efficiencies for H2 evolution under visible light. CATCH enumerates chemical coordination and writes reaction equations with sub-nanosecond precision.
CATCH employs density functional theory optimization and data mining prediction to select most probable heterojunctional peers from hetero/homo- dimensions. Through facile but efficient wet and dry synthesis, nanostructures will be bonded to basal planes or brinks of 2D slabs. CATCH benefits in-house techniques for product characterizations and refinements and emphasizes on cutting-edge in situ studies to unveil photocatalysis at advanced photon sources. Assisted with theoretical modelling, ambient and time-evolved experiments will illustrate photocatalytic dynamics and kinetics in mixed spacetime.
CATCH unites low-dimensional materials designs by counting physical and electronic merits from spacetime confinements. It metrologically elaborates photocatalysis in an elevated 2D+nD+t, alters passages of materials combinations crossing dimensions, and directs future photocatalyst designs. Standing on cross-dimensional materials innovation and photocatalysis study, CATCH breaks the deadlock of practical photocatalysis that eventually leads to sustainability.
Max ERC Funding
1 999 946 €
Duration
Start date: 2021-05-01, End date: 2026-04-30
Project acronym COMPLEX-FISH
Project Complex eco-evolutionary dynamics of aquatic ecosystems faced with human-induced and environmental stress
Researcher (PI) Anna KUPARINEN
Host Institution (HI) JYVASKYLAN YLIOPISTO
Country Finland
Call Details Consolidator Grant (CoG), LS8, ERC-2017-COG
Summary Resilience and recovery ability are key determinants of species persistence and viability in a changing world. Populations exposed to rapid environmental changes and human-induced alterations are often affected by both ecological and evolutionary processes and their interactions, that is, eco-evolutionary dynamics. The integrated perspective offered by eco-evolutionary dynamics is vital for understanding drivers of resilience and recovery of natural populations undergoing rapid changes and exposed to multiple stressors. However, the feedback mechanisms, and the ways in which evolution and phenotypic changes scale up to interacting species, communities, and ecosystems, remains poorly understood. The objective of my proposal is to bridge and close this gap by merging the fields of ecology and evolution into two interfaces of complex biological dynamics. I will do this in the context of conservation and sustainable harvesting of aquatic ecosystems. I will develop a novel mechanistic theory of eco-evolutionary ecosystem dynamics, by coupling the theory of allometric trophic networks with the theory of life-history evolution. I will analyse the eco-evolutionary dynamics of aquatic ecosystems to identify mechanisms responsible for species and ecosystem resilience and recovery ability. This will be done through systematic simulation studies and detailed analyses of three aquatic ecosystems. The project delves into the mechanisms through which anthropogenic and environmental drivers alter the eco-evolutionary dynamics of aquatic ecosystems. Mechanistic understanding of these dynamics, and their consequences to species and ecosystems, has great potential to resolve fundamental yet puzzling patterns observed in natural populations and to identify species and ecosystem properties regulating resilience and recovery ability. This will drastically change our ability to assess the risks related to current and future anthropogenic and environmental influences on aquatic ecosystems.
Summary
Resilience and recovery ability are key determinants of species persistence and viability in a changing world. Populations exposed to rapid environmental changes and human-induced alterations are often affected by both ecological and evolutionary processes and their interactions, that is, eco-evolutionary dynamics. The integrated perspective offered by eco-evolutionary dynamics is vital for understanding drivers of resilience and recovery of natural populations undergoing rapid changes and exposed to multiple stressors. However, the feedback mechanisms, and the ways in which evolution and phenotypic changes scale up to interacting species, communities, and ecosystems, remains poorly understood. The objective of my proposal is to bridge and close this gap by merging the fields of ecology and evolution into two interfaces of complex biological dynamics. I will do this in the context of conservation and sustainable harvesting of aquatic ecosystems. I will develop a novel mechanistic theory of eco-evolutionary ecosystem dynamics, by coupling the theory of allometric trophic networks with the theory of life-history evolution. I will analyse the eco-evolutionary dynamics of aquatic ecosystems to identify mechanisms responsible for species and ecosystem resilience and recovery ability. This will be done through systematic simulation studies and detailed analyses of three aquatic ecosystems. The project delves into the mechanisms through which anthropogenic and environmental drivers alter the eco-evolutionary dynamics of aquatic ecosystems. Mechanistic understanding of these dynamics, and their consequences to species and ecosystems, has great potential to resolve fundamental yet puzzling patterns observed in natural populations and to identify species and ecosystem properties regulating resilience and recovery ability. This will drastically change our ability to assess the risks related to current and future anthropogenic and environmental influences on aquatic ecosystems.
Max ERC Funding
1 999 391 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym CORKtheCAMBIA
Project Thickening of plant organs by nested stem cells
Researcher (PI) Ari Pekka MaeHoeNEN
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Consolidator Grant (CoG), LS3, ERC-2018-COG
Summary Growth originates from meristems, where stem cells are located. Lateral meristems, which provide thickness to tree stems and other plant organs, include vascular cambium (produces xylem [wood] and phloem); and cork cambium (forms cork, a tough protective layer).
We recently identified the molecular mechanism that specifies stem cells of vascular cambium. Unexpectedly, this same set of experiments revealed also novel aspects of the regulation of cork cambium, a meristem whose development has remained unknown. CORKtheCAMBIA aims to identify the stem cells of cork cambium and reveal how they mechanistically regulate plant organ thickening. Thus, stemming from these novel unpublished findings and my matching expertise on plant stem cells and lateral growth, the timing is perfect to discover the molecular mechanism underlying specification of stem cells of cork cambium.
To identify the origin of stem cells of cork cambium, 1st-we will combine lineage tracing with a detailed molecular marker analysis. To deduce the cell dynamics of cork cambium, 2nd-we will follow regeneration of the stem cells after ablation of this meristem. To discover the molecular factors regulating the stem cell specification of cork cambium, 3rd-we will utilize molecular genetics and a novel method (inducible CRISPR/Cas9 mutant targeting) being developed in my lab. Since the lateral growth is orchestrated by two adjacent, nested meristems, cork and vascular cambia, the growth process must be tightly co-regulated. Thus, 4th-an in silico model of the intertwined growth process will be generated. By combining modelling with experimentation, we will uncover mechanistically how cork and vascular cambium coordinate lateral growth.
CORKtheCAMBIA will thus provide long-awaited insight into the regulatory mechanisms specifying the stem cells of lateral meristem as whole, lay the foundation for studies on radial thickening and facilitate rational manipulation of lateral meristems of crop plants and trees.
Summary
Growth originates from meristems, where stem cells are located. Lateral meristems, which provide thickness to tree stems and other plant organs, include vascular cambium (produces xylem [wood] and phloem); and cork cambium (forms cork, a tough protective layer).
We recently identified the molecular mechanism that specifies stem cells of vascular cambium. Unexpectedly, this same set of experiments revealed also novel aspects of the regulation of cork cambium, a meristem whose development has remained unknown. CORKtheCAMBIA aims to identify the stem cells of cork cambium and reveal how they mechanistically regulate plant organ thickening. Thus, stemming from these novel unpublished findings and my matching expertise on plant stem cells and lateral growth, the timing is perfect to discover the molecular mechanism underlying specification of stem cells of cork cambium.
To identify the origin of stem cells of cork cambium, 1st-we will combine lineage tracing with a detailed molecular marker analysis. To deduce the cell dynamics of cork cambium, 2nd-we will follow regeneration of the stem cells after ablation of this meristem. To discover the molecular factors regulating the stem cell specification of cork cambium, 3rd-we will utilize molecular genetics and a novel method (inducible CRISPR/Cas9 mutant targeting) being developed in my lab. Since the lateral growth is orchestrated by two adjacent, nested meristems, cork and vascular cambia, the growth process must be tightly co-regulated. Thus, 4th-an in silico model of the intertwined growth process will be generated. By combining modelling with experimentation, we will uncover mechanistically how cork and vascular cambium coordinate lateral growth.
CORKtheCAMBIA will thus provide long-awaited insight into the regulatory mechanisms specifying the stem cells of lateral meristem as whole, lay the foundation for studies on radial thickening and facilitate rational manipulation of lateral meristems of crop plants and trees.
Max ERC Funding
1 999 752 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym Elephant Project
Project How elephants grow old
Researcher (PI) Virpi Annikki Lummaa
Host Institution (HI) TURUN YLIOPISTO
Country Finland
Call Details Consolidator Grant (CoG), LS8, ERC-2014-CoG
Summary The ageing population structure of most European countries has major health, economic and social consequences that lead to a need to better understand both the evolutionary limitations of deferring ageing, as well as the mechanisms involved in growing old. Ageing involves reduced fertility, mobility and ability to combat disease, but some individuals cope with growing old better than others. Improving the quality of life at old age and predicting future changes in longevity patterns of societies might depend on our ability to develop indicators of how old we really are and how many healthy years we have ahead, and how those indicators depend on our health history across several decades. Yet, most model species used in biology are short-lived and provide a poor comparison to long-lived mammals such as humans. Further, they do not often inform on the mechanisms of ageing alongside its fitness consequences in natural populations of long-lived mammals. This project integrates different ageing mechanisms with unique data on lifelong disease and reproductive history in the most long-lived non-human mammal studied so far, the Asian elephant. I will examine how different mechanisms of ageing (telomere dynamics, oxidative stress and telomerase activity) interact with lifelong disease and reproductive history, and current endocrinological measures of stress and reproductive status. This will help us to better understand both the mechanisms of ageing and their consequences on senescence rates. To do so, I will combine the most comprehensive demographic data (N~10.000) on Asian elephants in the world with bi-monthly health assessments and disease records across life (N~2500) and with longitudinal markers of ageing and hormonal correlates of stress and reproductive potential (N~240). Understanding changes in health across life and its links to ageing rates, stress levels and life-history in a species as long-lived as humans will be relevant to a large range of end-users.
Summary
The ageing population structure of most European countries has major health, economic and social consequences that lead to a need to better understand both the evolutionary limitations of deferring ageing, as well as the mechanisms involved in growing old. Ageing involves reduced fertility, mobility and ability to combat disease, but some individuals cope with growing old better than others. Improving the quality of life at old age and predicting future changes in longevity patterns of societies might depend on our ability to develop indicators of how old we really are and how many healthy years we have ahead, and how those indicators depend on our health history across several decades. Yet, most model species used in biology are short-lived and provide a poor comparison to long-lived mammals such as humans. Further, they do not often inform on the mechanisms of ageing alongside its fitness consequences in natural populations of long-lived mammals. This project integrates different ageing mechanisms with unique data on lifelong disease and reproductive history in the most long-lived non-human mammal studied so far, the Asian elephant. I will examine how different mechanisms of ageing (telomere dynamics, oxidative stress and telomerase activity) interact with lifelong disease and reproductive history, and current endocrinological measures of stress and reproductive status. This will help us to better understand both the mechanisms of ageing and their consequences on senescence rates. To do so, I will combine the most comprehensive demographic data (N~10.000) on Asian elephants in the world with bi-monthly health assessments and disease records across life (N~2500) and with longitudinal markers of ageing and hormonal correlates of stress and reproductive potential (N~240). Understanding changes in health across life and its links to ageing rates, stress levels and life-history in a species as long-lived as humans will be relevant to a large range of end-users.
Max ERC Funding
1 949 316 €
Duration
Start date: 2016-01-01, End date: 2021-12-31
Project acronym M-Imm
Project Novel etiology of autoimmune disorders: the role of acquired somatic mutations in lymphoid cells
Researcher (PI) Satu Maarit Mustjoki
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Consolidator Grant (CoG), LS6, ERC-2014-CoG
Summary Molecular pathogenesis of most immune-mediated disorders, such as of autoimmune diseases, is poorly understood. These common maladies carry a heavy burden both on patients and on society. Current therapy is non-targeted and results in significant short- and long-term adverse effects.
Large granular lymphocyte (LGL) leukemia is characterized by expansion of cytotoxic T- or NK-cells and represents an intriguing clinical continuum between a neoplastic and an autoimmune disorder. Patients suffer from autoimmune cytopenias and rheumatoid arthritis (RA), which are thought to be mediated by LGL cells targeting host tissues. My group recently discovered that 40-50% of LGL leukemia patients carry in their lymphoid cells acquired, activating mutations in the STAT3 gene – a key regulator of immune and oncogenic processes (Koskela et al, N Engl J Med, 2012). This breakthrough discovery gives insight to the pathogenesis of autoimmune disorders at large.
I present here a hypothesis that a strong antigen-induced proliferation is a mutational driver, which causes somatic mutations in lymphoid cells. When mutations hit key activating pathways, autoreactive cells acquire functional advantage and expand. The target antigen of the expanded clone determines the clinical characteristics of the autoimmune disease induced.
To prove this hypothesis, we will separate small lymphocyte clones from patients with autoimmune diseases and use sensitive next-generation sequencing methods to characterize the spectrum of somatic mutations in lymphoid cells. Further, we will study the function of mutated lymphocytes and examine the mechanisms of autocytotoxicity and end-organ/tissue damage. Finally, we aim to understand factors, which induce somatic mutations in lymphoid cells, such as the role of viral infections.
The results will transform our understanding of molecular pathogenesis of autoimmune diseases and lead to accurate diagnostics and discovery of novel drug targets.
Summary
Molecular pathogenesis of most immune-mediated disorders, such as of autoimmune diseases, is poorly understood. These common maladies carry a heavy burden both on patients and on society. Current therapy is non-targeted and results in significant short- and long-term adverse effects.
Large granular lymphocyte (LGL) leukemia is characterized by expansion of cytotoxic T- or NK-cells and represents an intriguing clinical continuum between a neoplastic and an autoimmune disorder. Patients suffer from autoimmune cytopenias and rheumatoid arthritis (RA), which are thought to be mediated by LGL cells targeting host tissues. My group recently discovered that 40-50% of LGL leukemia patients carry in their lymphoid cells acquired, activating mutations in the STAT3 gene – a key regulator of immune and oncogenic processes (Koskela et al, N Engl J Med, 2012). This breakthrough discovery gives insight to the pathogenesis of autoimmune disorders at large.
I present here a hypothesis that a strong antigen-induced proliferation is a mutational driver, which causes somatic mutations in lymphoid cells. When mutations hit key activating pathways, autoreactive cells acquire functional advantage and expand. The target antigen of the expanded clone determines the clinical characteristics of the autoimmune disease induced.
To prove this hypothesis, we will separate small lymphocyte clones from patients with autoimmune diseases and use sensitive next-generation sequencing methods to characterize the spectrum of somatic mutations in lymphoid cells. Further, we will study the function of mutated lymphocytes and examine the mechanisms of autocytotoxicity and end-organ/tissue damage. Finally, we aim to understand factors, which induce somatic mutations in lymphoid cells, such as the role of viral infections.
The results will transform our understanding of molecular pathogenesis of autoimmune diseases and lead to accurate diagnostics and discovery of novel drug targets.
Max ERC Funding
2 047 337 €
Duration
Start date: 2015-09-01, End date: 2021-02-28
Project acronym PARTIFACE
Project Green Route to Wood-Derived Janus Particles for Stabilized Interfaces
Researcher (PI) Kirsi MIKKONEN
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Consolidator Grant (CoG), PE8, ERC-2019-COG
Summary Emulsions are elemental to many aspects of every-day life, from food to pharmaceuticals. However, today’s emulsion science faces a grand challenge in developing stabilizers with outstanding functionality in a sustainable manner. To enable society’s transformation from oil-based economy to bioeconomy, there is an urgent need to develop sophisticated biocompatible materials, such as stabilizers of food and non-food emulsions, from biomass-derived precursors through sustainable conversion routes. Current bio-based stabilizers are poorly defined and not as efficient as the synthetic ones, primarily because key technologies to construct sophisticated hierarchical structures from abundant biopolymers are lacking. I will use my expertise on wood biomass and emulsion stabilizer research to develop a novel approach for asymmetric, bi-facial “Janus” nanoparticles from two of the most abundant, but underused biopolymers: lignin and hemicelluloses. I will develop a green conversion route using enzymatic crosslinking to build a novel concept: tailored wood-based Janus particles with superior capacity to stabilize emulsion interfaces. I will further tailor the particles to control their cooling rate through reversible bond formation, which will revolutionize the materials science. To achieve this ambitious goal, it is crucial to carefully characterize the particles and formed interfaces. I will develop a novel method to characterize real emulsion systems with high precision, which existing methods cannot achieve. PARTIFACE will establish a green route to sophisticated hierarchical architectures—bi-facial Janus-particle-stabilized interfaces—and thermal control systems utilizing abundant bioresources. The project will lead to a breakthrough in colloid and interface science and contribute to more sustainable use of Earth’s resources.
Summary
Emulsions are elemental to many aspects of every-day life, from food to pharmaceuticals. However, today’s emulsion science faces a grand challenge in developing stabilizers with outstanding functionality in a sustainable manner. To enable society’s transformation from oil-based economy to bioeconomy, there is an urgent need to develop sophisticated biocompatible materials, such as stabilizers of food and non-food emulsions, from biomass-derived precursors through sustainable conversion routes. Current bio-based stabilizers are poorly defined and not as efficient as the synthetic ones, primarily because key technologies to construct sophisticated hierarchical structures from abundant biopolymers are lacking. I will use my expertise on wood biomass and emulsion stabilizer research to develop a novel approach for asymmetric, bi-facial “Janus” nanoparticles from two of the most abundant, but underused biopolymers: lignin and hemicelluloses. I will develop a green conversion route using enzymatic crosslinking to build a novel concept: tailored wood-based Janus particles with superior capacity to stabilize emulsion interfaces. I will further tailor the particles to control their cooling rate through reversible bond formation, which will revolutionize the materials science. To achieve this ambitious goal, it is crucial to carefully characterize the particles and formed interfaces. I will develop a novel method to characterize real emulsion systems with high precision, which existing methods cannot achieve. PARTIFACE will establish a green route to sophisticated hierarchical architectures—bi-facial Janus-particle-stabilized interfaces—and thermal control systems utilizing abundant bioresources. The project will lead to a breakthrough in colloid and interface science and contribute to more sustainable use of Earth’s resources.
Max ERC Funding
2 000 000 €
Duration
Start date: 2020-06-01, End date: 2025-05-31
Project acronym QUANTOM
Project Quantitative Tomography Using Coupled Physics of Waves
Researcher (PI) Tanja TARVAINEN
Host Institution (HI) ITA-SUOMEN YLIOPISTO
Country Finland
Call Details Consolidator Grant (CoG), PE8, ERC-2020-COG
Summary Tomographic images are a valuable tool in various applications of medicine and biomedicine, industry and in security applications. Although efficient tomographic imaging techniques exist, development of new modalities that would overcome the limitations of the existing techniques are required. Overall, there is a need for development of new tomographic techniques that would provide quantitative information of unknown parameters of interest, such as tomographic images on the concentration of molecules. In particular, information on the reliability of the tomographic images is required.
The objective of the project is to develop quantitative tomographic imaging technique based on coupled physics of waves. In coupled physics imaging, contrast and resolution originating from different physical phenomena are combined. In the project, light, microwaves and ultrasound, i.e. waves, will be utilised through photoacoustic, thermoacoustic and acousto-optic effects. These techniques will be developed to produce tomographic images with an outstanding quantitative contrast in the sense of statistical information and modelling of uncertainties, combined with superior resolution and imaging depth.
Most tomographic imaging techniques are ill-posed problems that need to be approached in the framework of inverse problems. In the project, a Bayesian approach to ill-posed inverse problems, which supports the quantitative nature of the problem, will be taken. In the project, mathematical modelling and computational methods will be developed in close connection with experimental system development. The research is founded on a strong understanding of the underlying physics of coupled physics problems, knowledge on instrumentation on the related fields and experimental tomography, and state-of-the-art methods of computational inverse mathematics, that all come together in the PI’s research group.
Summary
Tomographic images are a valuable tool in various applications of medicine and biomedicine, industry and in security applications. Although efficient tomographic imaging techniques exist, development of new modalities that would overcome the limitations of the existing techniques are required. Overall, there is a need for development of new tomographic techniques that would provide quantitative information of unknown parameters of interest, such as tomographic images on the concentration of molecules. In particular, information on the reliability of the tomographic images is required.
The objective of the project is to develop quantitative tomographic imaging technique based on coupled physics of waves. In coupled physics imaging, contrast and resolution originating from different physical phenomena are combined. In the project, light, microwaves and ultrasound, i.e. waves, will be utilised through photoacoustic, thermoacoustic and acousto-optic effects. These techniques will be developed to produce tomographic images with an outstanding quantitative contrast in the sense of statistical information and modelling of uncertainties, combined with superior resolution and imaging depth.
Most tomographic imaging techniques are ill-posed problems that need to be approached in the framework of inverse problems. In the project, a Bayesian approach to ill-posed inverse problems, which supports the quantitative nature of the problem, will be taken. In the project, mathematical modelling and computational methods will be developed in close connection with experimental system development. The research is founded on a strong understanding of the underlying physics of coupled physics problems, knowledge on instrumentation on the related fields and experimental tomography, and state-of-the-art methods of computational inverse mathematics, that all come together in the PI’s research group.
Max ERC Funding
2 000 000 €
Duration
Start date: 2021-06-01, End date: 2026-05-31
