Project acronym DIADRUG
Project Insulin resistance and diabetic nephropathy - development of novel in vivo models for drug discovery
Researcher (PI) Sanna Lehtonen
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), LS9, ERC-2009-StG
Summary Up to one third of diabetic patients develop nephropathy, a serious complication of diabetes. Microalbuminuria is the earliest sign of the complication, which may ultimately develop to end-stage renal disease requiring dialysis or a kidney transplant. Insulin resistance and metabolic syndrome are associated with an increased risk for diabetic nephropathy. Interestingly, glomerular epithelial cells or podocytes have recently been shown to be insulin responsive. Further, nephrin, a key structural component of podocytes, is essential for insulin action in these cells. Our novel findings show that adaptor protein CD2AP, an interaction partner of nephrin, associates with regulators of insulin signaling and glucose transport in glomeruli. The results suggest that nephrin and CD2AP are involved, by association with these proteins, in the regulation of insulin signaling and glucose transport in podocytes. We hypothesize that podocytes can develop insulin resistance and that disturbances in insulin response affect podocyte function and contribute to the development of diabetic nephropathy. The aim of this project is to clarify the mechanisms leading to development of insulin resistance in podocytes and to study the association between insulin resistance and the development of diabetic nephropathy. For this we will develop transgenic zebrafish and mouse models by overexpressing/knocking down insulin signaling-associated proteins specifically in podocytes. Further, we aim to identify novel drug leads to treat insulin resistance and diabetic nephropathy by performing high-throughput small molecule library screens on the developed transgenic fish models. The ultimate goal is to find a treatment to combat the early stages of diabetic nephropathy in humans.
Summary
Up to one third of diabetic patients develop nephropathy, a serious complication of diabetes. Microalbuminuria is the earliest sign of the complication, which may ultimately develop to end-stage renal disease requiring dialysis or a kidney transplant. Insulin resistance and metabolic syndrome are associated with an increased risk for diabetic nephropathy. Interestingly, glomerular epithelial cells or podocytes have recently been shown to be insulin responsive. Further, nephrin, a key structural component of podocytes, is essential for insulin action in these cells. Our novel findings show that adaptor protein CD2AP, an interaction partner of nephrin, associates with regulators of insulin signaling and glucose transport in glomeruli. The results suggest that nephrin and CD2AP are involved, by association with these proteins, in the regulation of insulin signaling and glucose transport in podocytes. We hypothesize that podocytes can develop insulin resistance and that disturbances in insulin response affect podocyte function and contribute to the development of diabetic nephropathy. The aim of this project is to clarify the mechanisms leading to development of insulin resistance in podocytes and to study the association between insulin resistance and the development of diabetic nephropathy. For this we will develop transgenic zebrafish and mouse models by overexpressing/knocking down insulin signaling-associated proteins specifically in podocytes. Further, we aim to identify novel drug leads to treat insulin resistance and diabetic nephropathy by performing high-throughput small molecule library screens on the developed transgenic fish models. The ultimate goal is to find a treatment to combat the early stages of diabetic nephropathy in humans.
Max ERC Funding
2 000 000 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym FUTUREGENES
Project Gene transfer techniques in the treatment of cardiovascular diseases and malignant glioma
Researcher (PI) Seppo Yla-Herttuala
Host Institution (HI) ITA-SUOMEN YLIOPISTO
Call Details Advanced Grant (AdG), LS7, ERC-2009-AdG
Summary Background: Poor angiogenesis and collateral vessel formation lead to coronary heart disease, claudication, infarctions and amputations while malignant glioma is one of the most aggressive proangiogenic tumors leading to death in a few months. For these diseases either stimulation or blocking, respectively, of angiogenesis may provide novel treatment options. Advancing State-of-the-Art: Our hypothesis is that in ischemia it will be possible to support natural growth of blood vessels with Therapeutic angiogenesis and lymphangiogenesis by using local gene transfer of the new members of vascular endothelial growth factor (VEGF) family and their receptors. New co-receptors, designer mutants and PCR suffling products of VEGFs will be used. New vector technology will be used to achieve long-lasting effects of VEGFs. We aim to develop novel site-specifically integrating, targeted, regulated vectors to precisely express the new VEGFs, their soluble decoy receptors and single-chain therapeutic antibodies (scFv) for pro- and anti-angiogenic purposes. As novel approaches, we have developed metabolically biotinylated lenti- and adenoviruses suitable for targeting and Epigenetherapy where siRNA/miRNAs and short nuclear RNAs regulate endogenous gene expression at the VEGF promoter level via modification of histone code. scFv library for endothelial cells and lentivirus-siRNA library directed to all human and mouse kinases will be screened to identify new mediators of angiogenesis in order to develop next generation pro- and antiangiogenic therapies. Based on our strong track record in Clinical applications, the best new pro- and antiangiogenic approaches will be taken to phase I clinical studies in myocardial ischemia and malignant glioma. Significance: This work should lead to significant advances and new therapies for severe ischemia and malignant glioma. Epigenetherapy and new site-specifically integrating, regulated vectors should be widely applicable in medicine.
Summary
Background: Poor angiogenesis and collateral vessel formation lead to coronary heart disease, claudication, infarctions and amputations while malignant glioma is one of the most aggressive proangiogenic tumors leading to death in a few months. For these diseases either stimulation or blocking, respectively, of angiogenesis may provide novel treatment options. Advancing State-of-the-Art: Our hypothesis is that in ischemia it will be possible to support natural growth of blood vessels with Therapeutic angiogenesis and lymphangiogenesis by using local gene transfer of the new members of vascular endothelial growth factor (VEGF) family and their receptors. New co-receptors, designer mutants and PCR suffling products of VEGFs will be used. New vector technology will be used to achieve long-lasting effects of VEGFs. We aim to develop novel site-specifically integrating, targeted, regulated vectors to precisely express the new VEGFs, their soluble decoy receptors and single-chain therapeutic antibodies (scFv) for pro- and anti-angiogenic purposes. As novel approaches, we have developed metabolically biotinylated lenti- and adenoviruses suitable for targeting and Epigenetherapy where siRNA/miRNAs and short nuclear RNAs regulate endogenous gene expression at the VEGF promoter level via modification of histone code. scFv library for endothelial cells and lentivirus-siRNA library directed to all human and mouse kinases will be screened to identify new mediators of angiogenesis in order to develop next generation pro- and antiangiogenic therapies. Based on our strong track record in Clinical applications, the best new pro- and antiangiogenic approaches will be taken to phase I clinical studies in myocardial ischemia and malignant glioma. Significance: This work should lead to significant advances and new therapies for severe ischemia and malignant glioma. Epigenetherapy and new site-specifically integrating, regulated vectors should be widely applicable in medicine.
Max ERC Funding
2 200 000 €
Duration
Start date: 2010-06-01, End date: 2015-05-31
Project acronym HEATTRONICS
Project Mesoscopic heattronics: thermal and nonequilibrium effects and fluctuations in nanoelectronics
Researcher (PI) Tero Tapio Heikkilä
Host Institution (HI) JYVASKYLAN YLIOPISTO
Call Details Starting Grant (StG), PE3, ERC-2009-StG
Summary Few systems in nature are entirely in equilibrium. Out of equilibrium, there are heat currents, and different degrees of freedom or parts of studied systems may be described by entirely different temperatures if the concept of temperature is at all well defined. In this project we will study the emergence of the subsystem temperatures in different types of small electronic systems, and the physical phenomena associated with those temperatures. Our emphasis is on the mesoscopic effects, residing between the microscopic world of individual atoms and electrons, and the macroscopic everyday world. In particular, we will research thermometry methods, different types of relaxation, magnitudes of fluctuations and effects at high frequencies. We will explore these effects in a wide variety of systems: normal metals and superconductors, carbon nanostructures, nanoelectromechanical and spintronic systems. Besides contributing to the understanding of the fundamental properties of electronic systems, our studies are directly relevant for the development of thermal sensors and electron refrigerators. The improved understanding of the thermal phenomena will also benefit the study of almost any type of a nonlinear phenomenon in electronics, for example the research of solid-state realizations of quantum computing or the race towards quantum limited mass and force detection.
Summary
Few systems in nature are entirely in equilibrium. Out of equilibrium, there are heat currents, and different degrees of freedom or parts of studied systems may be described by entirely different temperatures if the concept of temperature is at all well defined. In this project we will study the emergence of the subsystem temperatures in different types of small electronic systems, and the physical phenomena associated with those temperatures. Our emphasis is on the mesoscopic effects, residing between the microscopic world of individual atoms and electrons, and the macroscopic everyday world. In particular, we will research thermometry methods, different types of relaxation, magnitudes of fluctuations and effects at high frequencies. We will explore these effects in a wide variety of systems: normal metals and superconductors, carbon nanostructures, nanoelectromechanical and spintronic systems. Besides contributing to the understanding of the fundamental properties of electronic systems, our studies are directly relevant for the development of thermal sensors and electron refrigerators. The improved understanding of the thermal phenomena will also benefit the study of almost any type of a nonlinear phenomenon in electronics, for example the research of solid-state realizations of quantum computing or the race towards quantum limited mass and force detection.
Max ERC Funding
1 322 371 €
Duration
Start date: 2010-01-01, End date: 2015-12-31
Project acronym NEMSQED
Project Electromechanical quantum coherent systems
Researcher (PI) Mika Antero Sillanpää
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Call Details Starting Grant (StG), PE3, ERC-2009-StG
Summary At a low temperature, nearly macroscopic quantum states can be sustained in superconducting (SC) Josephson junctions. Recently, these superconducting qubits have been coupled to electromagnetic resonators, in a manner analogous to cavity Quantum Electro Dynamics (QED) which describes the interaction between atoms and quantized oscillation modes in the quantum limit. On the other hand, there is yet no experimental evidence of a mode of a mechanical oscillator, such as that of a miniaturized vibrating string, to be chilled down to its quantum ground state. The main part of the proposal involves the use the coupling of Nanomechanical Resonators (NR) to SC qubits employed as artificial atoms in order to address the quantum-classical interface in mechanical motion. Similarly as the SC qubit can exchange quanta with electrical oscillators, it can, in principle, communicate with mechanical modes. The research will begin with demonstrating this kind of electromechanical interaction. In order to tackle experimental surprises, I plan on launching two parallel paths, one with a charge qubit, the other using a phase qubit. The formidable main goal is to experimentally reach the quantum ground state of a mechanical mode. I will investigate the following routes: Make a 1 GHz frequency NR, corresponding to 50 mK, which will reach the ground state at accessible temperatures. On the other hand, I propose to side-band cool a lower-frequency NR via the attached SC qubit. Near the quantum limit, I will start taking advantage of the NR as a building block of electromechanical quantum information. I also propose to push the QED setup of SC qubits coupled to electrical cavities towards more and more complicated states in order to test quantum mechanics in the nearly classical limit.
Summary
At a low temperature, nearly macroscopic quantum states can be sustained in superconducting (SC) Josephson junctions. Recently, these superconducting qubits have been coupled to electromagnetic resonators, in a manner analogous to cavity Quantum Electro Dynamics (QED) which describes the interaction between atoms and quantized oscillation modes in the quantum limit. On the other hand, there is yet no experimental evidence of a mode of a mechanical oscillator, such as that of a miniaturized vibrating string, to be chilled down to its quantum ground state. The main part of the proposal involves the use the coupling of Nanomechanical Resonators (NR) to SC qubits employed as artificial atoms in order to address the quantum-classical interface in mechanical motion. Similarly as the SC qubit can exchange quanta with electrical oscillators, it can, in principle, communicate with mechanical modes. The research will begin with demonstrating this kind of electromechanical interaction. In order to tackle experimental surprises, I plan on launching two parallel paths, one with a charge qubit, the other using a phase qubit. The formidable main goal is to experimentally reach the quantum ground state of a mechanical mode. I will investigate the following routes: Make a 1 GHz frequency NR, corresponding to 50 mK, which will reach the ground state at accessible temperatures. On the other hand, I propose to side-band cool a lower-frequency NR via the attached SC qubit. Near the quantum limit, I will start taking advantage of the NR as a building block of electromechanical quantum information. I also propose to push the QED setup of SC qubits coupled to electrical cavities towards more and more complicated states in order to test quantum mechanics in the nearly classical limit.
Max ERC Funding
1 373 000 €
Duration
Start date: 2010-01-01, End date: 2014-12-31
Project acronym SMARTBAYES
Project Intelligent Stochastic Computation Methods for Complex Statistical Model Learning
Researcher (PI) Jukka Ilmari Corander
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), PE1, ERC-2009-StG
Summary Very recently, it has been claimed that the Bayesian paradigm has revolutionized statistical thinking in numerous fields of research, as a considerable amount of novel Bayesian statistical models and estimation algorithms have gained popularity among scientists. Despite of the evident success of the Bayesian approach, there are also many research problems where the computational challenges have so far proven to be too exhaustive to promote wide-spread use of the state-of-the-art Bayesian methodology. In particular, due to significant advances in measurement technologies, e.g. in molecular biology, a constant need for analyzing and modeling very large and complex data sets has emerged on a wide scale during the past decade. Such needs are even anticipated to rapidly increase in near future with the current technological advances. The prevailing situation is therefore somewhat paradoxical, as the theoretical superiority of the Bayesian paradigm as an uncertainty handling framework is widely acknowledged, yet it can be unable to provide practically applicable solutions to complex scientific problems. To resolve this issue, the research project will have a focus on stochastic computational and modeling strategies to develop methods that overcome problems associated with the analysis of highly complex data sets. With these methods we aim to be able to solve a multitude of statistical learning problems for data sets which cannot yet be reliably handled in practice by any of the existing Bayesian tools. Our approaches will build upon recent advances in Bayesian predictive modeling and adaptive stochastic Monte Carlo computation, to create a novel family of parallel interacting learning algorithms. Several significant statistical modeling problems will be considered to demonstrate the potential of the developed methods. Our goal is also to provide implementations of some of the algorithms as freely available software packages to benefit concretely the scientific community.
Summary
Very recently, it has been claimed that the Bayesian paradigm has revolutionized statistical thinking in numerous fields of research, as a considerable amount of novel Bayesian statistical models and estimation algorithms have gained popularity among scientists. Despite of the evident success of the Bayesian approach, there are also many research problems where the computational challenges have so far proven to be too exhaustive to promote wide-spread use of the state-of-the-art Bayesian methodology. In particular, due to significant advances in measurement technologies, e.g. in molecular biology, a constant need for analyzing and modeling very large and complex data sets has emerged on a wide scale during the past decade. Such needs are even anticipated to rapidly increase in near future with the current technological advances. The prevailing situation is therefore somewhat paradoxical, as the theoretical superiority of the Bayesian paradigm as an uncertainty handling framework is widely acknowledged, yet it can be unable to provide practically applicable solutions to complex scientific problems. To resolve this issue, the research project will have a focus on stochastic computational and modeling strategies to develop methods that overcome problems associated with the analysis of highly complex data sets. With these methods we aim to be able to solve a multitude of statistical learning problems for data sets which cannot yet be reliably handled in practice by any of the existing Bayesian tools. Our approaches will build upon recent advances in Bayesian predictive modeling and adaptive stochastic Monte Carlo computation, to create a novel family of parallel interacting learning algorithms. Several significant statistical modeling problems will be considered to demonstrate the potential of the developed methods. Our goal is also to provide implementations of some of the algorithms as freely available software packages to benefit concretely the scientific community.
Max ERC Funding
550 000 €
Duration
Start date: 2009-11-01, End date: 2014-10-31
Project acronym TEPESS
Project Technologies and psychophysics of spatial sound
Researcher (PI) Ville Pulkki
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Call Details Starting Grant (StG), PE7, ERC-2009-StG
Summary Spatial audio is a field, which investigates technologies to capture and reproduce sound in a way that the spatial properties of it are either preserved or modified depending on application. For example, modern surround sound techniques try to reproduce the sound scene perceived by a human listener in the same way than in the original occasion. The principal investigator (PI) has been able to develop a number of technologies in spatial audio field and to transfer them to the industry. The project would have two work packages, one concentrating on development of technology (WP1) and the other on perceptual studies (WP2). The perceptual studies are assumed to help technology development, and new technologies are assumed to reveal new phenomena in perception. The main issue for WP1 is the development of generic audio format. In future all music records and movie audio tracks are targeted to be in this format, which would be suitable for listening with any loudspeaker setup and also with headphones, always with optimal spatial and timbral quality. The development of the format is based on a technique by the PI, which is extended in this work for enhanced playback over loudspeakers and over headphones. Also, new techniques are developed for sound input from different types of microphones and from existing audio formats. The perceptual issues studied in WP2 would be the functioning of spatial hearing with wide sources and complex sound scenarios, together with computational modeling of brain mechanisms devoted to binaural hearing. The crossmodal effects between vision and auditory systems would also be investigated in the anechoic chamber specially equipped for spatial sound research. As the final task, the perceptual quality of developed generic audio format in different listening scenarios would be evaluated with subjective and objective tests.
Summary
Spatial audio is a field, which investigates technologies to capture and reproduce sound in a way that the spatial properties of it are either preserved or modified depending on application. For example, modern surround sound techniques try to reproduce the sound scene perceived by a human listener in the same way than in the original occasion. The principal investigator (PI) has been able to develop a number of technologies in spatial audio field and to transfer them to the industry. The project would have two work packages, one concentrating on development of technology (WP1) and the other on perceptual studies (WP2). The perceptual studies are assumed to help technology development, and new technologies are assumed to reveal new phenomena in perception. The main issue for WP1 is the development of generic audio format. In future all music records and movie audio tracks are targeted to be in this format, which would be suitable for listening with any loudspeaker setup and also with headphones, always with optimal spatial and timbral quality. The development of the format is based on a technique by the PI, which is extended in this work for enhanced playback over loudspeakers and over headphones. Also, new techniques are developed for sound input from different types of microphones and from existing audio formats. The perceptual issues studied in WP2 would be the functioning of spatial hearing with wide sources and complex sound scenarios, together with computational modeling of brain mechanisms devoted to binaural hearing. The crossmodal effects between vision and auditory systems would also be investigated in the anechoic chamber specially equipped for spatial sound research. As the final task, the perceptual quality of developed generic audio format in different listening scenarios would be evaluated with subjective and objective tests.
Max ERC Funding
1 879 458 €
Duration
Start date: 2009-09-01, End date: 2014-08-31
Project acronym TLIM
Project Talent and Learning in Imperfect Markets
Researcher (PI) Marko Juhani Terviö
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Call Details Starting Grant (StG), SH1, ERC-2009-StG
Summary The overall effectiveness at which the underlying talent resources in an economy are utilized is an important determinant of long-run economic growth and well-being. Recent work has shown that the processes through which talent is discovered and revealed in the economy are likely to suffer from market imperfections that are analogous to problems that have been for long been understood in the context of private provision of job training and education, resulting in not just reduced economic efficiency but also contributing to income inequality. The first basic question is what is the role of talent rents in explaining income inequality? In a static world where all information about talent is known, such talent rents would merely be compensation to a scarce factor of production. However, when the discovery of talent is subject to market imperfections then income differences that ostensibly look like talent rents are partly due to inefficient information rents. This raises the second and novel question, about whether and to what extent observed income differences are due to inefficient rents to information about talent that masquerade as talent rents. I also plan to investigate how technological change has impacted the distribution of talent rents via its effect on the discovery/revelation process of talent. The larger goal of the project is to help understand the economy-wide implications of institutions and policies that govern the discovery and allocation of talent in the economy. Better understanding could also point the way towards improved policy interventions.
Summary
The overall effectiveness at which the underlying talent resources in an economy are utilized is an important determinant of long-run economic growth and well-being. Recent work has shown that the processes through which talent is discovered and revealed in the economy are likely to suffer from market imperfections that are analogous to problems that have been for long been understood in the context of private provision of job training and education, resulting in not just reduced economic efficiency but also contributing to income inequality. The first basic question is what is the role of talent rents in explaining income inequality? In a static world where all information about talent is known, such talent rents would merely be compensation to a scarce factor of production. However, when the discovery of talent is subject to market imperfections then income differences that ostensibly look like talent rents are partly due to inefficient information rents. This raises the second and novel question, about whether and to what extent observed income differences are due to inefficient rents to information about talent that masquerade as talent rents. I also plan to investigate how technological change has impacted the distribution of talent rents via its effect on the discovery/revelation process of talent. The larger goal of the project is to help understand the economy-wide implications of institutions and policies that govern the discovery and allocation of talent in the economy. Better understanding could also point the way towards improved policy interventions.
Max ERC Funding
1 003 440 €
Duration
Start date: 2009-10-01, End date: 2015-03-31
