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
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 CAVITYQPD
Project Cavity quantum phonon dynamics
Researcher (PI) Mika Antero Sillanpää
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Call Details Consolidator Grant (CoG), PE3, ERC-2013-CoG
Summary "Large bodies usually follow the classical equations of motion. Deviations from this can be called
macroscopic quantum behavior. These phenomena have been experimentally verified with cavity Quantum
Electro Dynamics (QED), trapped ions, and superconducting Josephson junction systems. Recently, evidence
was obtained that also moving objects can display such behavior. These objects are micromechanical
resonators (MR), which can measure tens of microns in size and are hence quite macroscopic. The degree of
freedom is their vibrations: phonons.
I propose experimental research in order to push quantum mechanics closer to the classical world than ever
before. I will try find quantum behavior in the most classical objects, that is, slowly moving bodies. I will use
MR's, accessed via electrical resonators. Part of it will be in analogy to the previously studied macroscopic
systems, but with photons replaced by phonons. The experiments are done in a cryogenic temperature mostly
in dilution refrigerator. The work will open up new perspectives on how nature works, and can have
technological implications.
The first basic setup is the coupling of MR to microwave cavity resonators. This is a direct analogy to
optomechanics, and can be called circuit optomechanics. The goals will be phonon state transfer via a cavity
bus, construction of squeezed states and of phonon-cavity entanglement. The second setup is to boost the
optomechanical coupling with a Josephson junction system, and reach the single-phonon strong-coupling for
the first time. The third setup is the coupling of MR to a Josephson junction artificial atom. Here we will
access the MR same way as the motion of a trapped ions is coupled to their internal transitions. In this setup,
I am proposing to construct exotic quantum states of motion, and finally entangle and transfer phonons over
mm-distance via cavity-coupled qubits. I believe within the project it is possible to perform rudimentary Bell
measurement with phonons."
Summary
"Large bodies usually follow the classical equations of motion. Deviations from this can be called
macroscopic quantum behavior. These phenomena have been experimentally verified with cavity Quantum
Electro Dynamics (QED), trapped ions, and superconducting Josephson junction systems. Recently, evidence
was obtained that also moving objects can display such behavior. These objects are micromechanical
resonators (MR), which can measure tens of microns in size and are hence quite macroscopic. The degree of
freedom is their vibrations: phonons.
I propose experimental research in order to push quantum mechanics closer to the classical world than ever
before. I will try find quantum behavior in the most classical objects, that is, slowly moving bodies. I will use
MR's, accessed via electrical resonators. Part of it will be in analogy to the previously studied macroscopic
systems, but with photons replaced by phonons. The experiments are done in a cryogenic temperature mostly
in dilution refrigerator. The work will open up new perspectives on how nature works, and can have
technological implications.
The first basic setup is the coupling of MR to microwave cavity resonators. This is a direct analogy to
optomechanics, and can be called circuit optomechanics. The goals will be phonon state transfer via a cavity
bus, construction of squeezed states and of phonon-cavity entanglement. The second setup is to boost the
optomechanical coupling with a Josephson junction system, and reach the single-phonon strong-coupling for
the first time. The third setup is the coupling of MR to a Josephson junction artificial atom. Here we will
access the MR same way as the motion of a trapped ions is coupled to their internal transitions. In this setup,
I am proposing to construct exotic quantum states of motion, and finally entangle and transfer phonons over
mm-distance via cavity-coupled qubits. I believe within the project it is possible to perform rudimentary Bell
measurement with phonons."
Max ERC Funding
2 004 283 €
Duration
Start date: 2015-01-01, End date: 2019-12-31
Project acronym CORKtheCAMBIA
Project Thickening of plant organs by nested stem cells
Researcher (PI) Ari Pekka MÄHÖNEN
Host Institution (HI) HELSINGIN YLIOPISTO
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 QUESS
Project Quantum Environment Engineering for Steered Systems
Researcher (PI) Mikko Pentti Matias Möttönen
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Call Details Consolidator Grant (CoG), PE3, ERC-2015-CoG
Summary The superconducting quantum computer has very recently reached the theoretical thresholds for fault-tolerant universal quantum computing and a quantum annealer based on superconducting quantum bits, qubits, is already commercially available. However, several fundamental questions on the way to efficient large-scale quantum computing have to be answered: qubit initialization, extreme gate accuracy, and quantum-level power consumption.
This project, QUESS, aims for a breakthrough in the realization and control of dissipative environments for quantum devices. Based on novel concepts for normal-metal components integrated with superconducting quantum nanoelectronics, we experimentally realize in-situ-tunable low-temperature environments for superconducting qubits. These environments can be used to precisely reset qubits at will, thus providing an ideal initialization scheme for the quantum computer. The environment can also be well decoupled from the qubit to allow for coherent quantum computing. Utilizing this base technology, we find fundamental quantum-mechanical limitations to the accuracy and power consumption in quantum control, and realize optimal strategies to achieve these limits in practice. Finally, we build a concept of a universal quantum simulator for non-Markovian open quantum systems and experimentally realize its basic building blocks.
This proposal provides key missing ingredients in realizing efficient large-scale quantum computers ultimately leading to a quantum technological revolution, with envisioned practical applications in materials and drug design, energy harvesting, artificial intelligence, telecommunications, and internet of things. Furthermore, this project opens fruitful horizons for tunable environments in quantum technology beyond the superconducting quantum computer, for applications of quantum-limited control, for quantum annealing, and for simulators of non-Markovian open quantum systems.
Summary
The superconducting quantum computer has very recently reached the theoretical thresholds for fault-tolerant universal quantum computing and a quantum annealer based on superconducting quantum bits, qubits, is already commercially available. However, several fundamental questions on the way to efficient large-scale quantum computing have to be answered: qubit initialization, extreme gate accuracy, and quantum-level power consumption.
This project, QUESS, aims for a breakthrough in the realization and control of dissipative environments for quantum devices. Based on novel concepts for normal-metal components integrated with superconducting quantum nanoelectronics, we experimentally realize in-situ-tunable low-temperature environments for superconducting qubits. These environments can be used to precisely reset qubits at will, thus providing an ideal initialization scheme for the quantum computer. The environment can also be well decoupled from the qubit to allow for coherent quantum computing. Utilizing this base technology, we find fundamental quantum-mechanical limitations to the accuracy and power consumption in quantum control, and realize optimal strategies to achieve these limits in practice. Finally, we build a concept of a universal quantum simulator for non-Markovian open quantum systems and experimentally realize its basic building blocks.
This proposal provides key missing ingredients in realizing efficient large-scale quantum computers ultimately leading to a quantum technological revolution, with envisioned practical applications in materials and drug design, energy harvesting, artificial intelligence, telecommunications, and internet of things. Furthermore, this project opens fruitful horizons for tunable environments in quantum technology beyond the superconducting quantum computer, for applications of quantum-limited control, for quantum annealing, and for simulators of non-Markovian open quantum systems.
Max ERC Funding
1 949 570 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym STEMpop
Project Mechanisms of stem cell population dynamics and reprogramming
Researcher (PI) Sara WICKSTRÖM
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Consolidator Grant (CoG), LS3, ERC-2017-COG
Summary How complex but stereotyped tissues are formed, maintained and regenerated through local growth, differentiation and remodeling is a fundamental open question in biology. Understanding how single cell behaviors are coordinated on the population level and how population-level dynamics is coupled to tissue architecture is required to resolve this question as well as to develop stem cell (SC) therapies and effective treatments against cancers.
As a self-renewing organ maintained by multiple distinct SC populations, the epidermis represents an outstanding, clinically highly relevant research paradigm to address this question. A key epidermal SC population are the hair follicle stem cells (HFSCs) that fuel hair follicle regeneration, repair epidermal injuries and, when deregulated, initiate carcinogenesis. The major obstacle in mechanistic understanding of HFSC regulation has been the lack of an in vitro culture system enabling their precise monitoring and manipulation. We have overcome this barrier by developing a method for long-term maintenance of multipotent HFSCs that recapitulates the complexity of HFSC fate decisions and dynamic crosstalk between HFSCs and their progeny.
This breakthrough invention puts me in the unique position to investigate how HFSCs self-organize into a network of SCs and progenitors through population-level signaling crosstalk and phenotypic plasticity. This project will uncover the spatiotemporal dynamics of HFSCs fate decisions and establish the role of the niche in this process (Aim1), decipher key gene-regulatory networks and epigenetic barriers that control phenotypic plasticity (Aim2), and discover druggable signaling networks that drive bi-directional reprogramming of HFSCs and their progeny (Aim3). By deconstructing complex tissue-level behaviors at an unprecedented spatiotemporal resolution this study has the potential to transform the fundaments of adult SC biology with immediate implications to regenerative medicine.
Summary
How complex but stereotyped tissues are formed, maintained and regenerated through local growth, differentiation and remodeling is a fundamental open question in biology. Understanding how single cell behaviors are coordinated on the population level and how population-level dynamics is coupled to tissue architecture is required to resolve this question as well as to develop stem cell (SC) therapies and effective treatments against cancers.
As a self-renewing organ maintained by multiple distinct SC populations, the epidermis represents an outstanding, clinically highly relevant research paradigm to address this question. A key epidermal SC population are the hair follicle stem cells (HFSCs) that fuel hair follicle regeneration, repair epidermal injuries and, when deregulated, initiate carcinogenesis. The major obstacle in mechanistic understanding of HFSC regulation has been the lack of an in vitro culture system enabling their precise monitoring and manipulation. We have overcome this barrier by developing a method for long-term maintenance of multipotent HFSCs that recapitulates the complexity of HFSC fate decisions and dynamic crosstalk between HFSCs and their progeny.
This breakthrough invention puts me in the unique position to investigate how HFSCs self-organize into a network of SCs and progenitors through population-level signaling crosstalk and phenotypic plasticity. This project will uncover the spatiotemporal dynamics of HFSCs fate decisions and establish the role of the niche in this process (Aim1), decipher key gene-regulatory networks and epigenetic barriers that control phenotypic plasticity (Aim2), and discover druggable signaling networks that drive bi-directional reprogramming of HFSCs and their progeny (Aim3). By deconstructing complex tissue-level behaviors at an unprecedented spatiotemporal resolution this study has the potential to transform the fundaments of adult SC biology with immediate implications to regenerative medicine.
Max ERC Funding
1 999 918 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym UFLNMR
Project Ultrafast Laplace NMR
Researcher (PI) Ville-Veikko TELKKI
Host Institution (HI) OULUN YLIOPISTO
Call Details Consolidator Grant (CoG), PE4, ERC-2017-COG
Summary Laplace NMR (LNMR), comprising diffusion and relaxation NMR experiments, provides detailed information on the dynamics and chemical resolution of molecular systems, which is complementary to NMR spectra. Similarly to the traditional NMR spectroscopy, the information content of LNMR can be significantly enhanced by a multidimensional approach. The long experiment time and low sensitivity restrict the applicability of the multidimensional method, however. Based on spatial encoding of multidimensional data, we develop a broad range of single-scan LNMR experiments, constituting a new class of NMR experiments called ultrafast multidimensional LNMR. The method shortens the experiment time by one to three orders of magnitude as compared to the conventional method, offering unprecedented opportunity to study fast processes in real time. Furthermore, it enables boosting the sensitivity by several orders of magnitude by using nuclear spin hyperpolarization, which allows investigation of low-concentration samples. Ultrafast LNMR opens paradigm-breaking prospects in chemical, biochemical, geologic, archaeologic and medical analysis. LNMR can, e.g., provide unique information on the intra- and extracellular metabolic processes, including those of cancer cells, which facilitates diagnostics and helps to find efficient treatments, and it can be exploited in the development of new types of biosensors. Furthermore, the method reveals previously unobservable details about the phase behaviour of ionic liquids, gel and polymer formation, as well as catalysis, which are essential in understanding their performance in technological applications. LNMR is also applicable to portable, single-sided magnets, implying potential to raise the sensitivity of low-field NMR to a completely new level. This entails significant impact on mobile chemical and medical analysis. The low cost of the low-field facility renders advanced NMR analysis broadly available, even in developing countries.
Summary
Laplace NMR (LNMR), comprising diffusion and relaxation NMR experiments, provides detailed information on the dynamics and chemical resolution of molecular systems, which is complementary to NMR spectra. Similarly to the traditional NMR spectroscopy, the information content of LNMR can be significantly enhanced by a multidimensional approach. The long experiment time and low sensitivity restrict the applicability of the multidimensional method, however. Based on spatial encoding of multidimensional data, we develop a broad range of single-scan LNMR experiments, constituting a new class of NMR experiments called ultrafast multidimensional LNMR. The method shortens the experiment time by one to three orders of magnitude as compared to the conventional method, offering unprecedented opportunity to study fast processes in real time. Furthermore, it enables boosting the sensitivity by several orders of magnitude by using nuclear spin hyperpolarization, which allows investigation of low-concentration samples. Ultrafast LNMR opens paradigm-breaking prospects in chemical, biochemical, geologic, archaeologic and medical analysis. LNMR can, e.g., provide unique information on the intra- and extracellular metabolic processes, including those of cancer cells, which facilitates diagnostics and helps to find efficient treatments, and it can be exploited in the development of new types of biosensors. Furthermore, the method reveals previously unobservable details about the phase behaviour of ionic liquids, gel and polymer formation, as well as catalysis, which are essential in understanding their performance in technological applications. LNMR is also applicable to portable, single-sided magnets, implying potential to raise the sensitivity of low-field NMR to a completely new level. This entails significant impact on mobile chemical and medical analysis. The low cost of the low-field facility renders advanced NMR analysis broadly available, even in developing countries.
Max ERC Funding
2 625 000 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
