Project acronym ALK7
Project Metabolic control by the TGF-² superfamily receptor ALK7: A novel regulator of insulin secretion, fat accumulation and energy balance
Researcher (PI) Carlos Ibanez
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary The aim of this proposal is to understand a novel regulatory signaling network controlling insulin secretion, fat accumulation and energy balance centered around selected components of the TGF-² signaling system, including Activins A and B, GDF-3 and their receptors ALK7 and ALK4. Recent results from my laboratory indicate that these molecules are part of paracrine signaling networks that control important functions in pancreatic islets and adipose tissue through feedback inhibition and feed-forward regulation. These discoveries have open up a new research area with important implications for the understanding of metabolic networks and the treatment of human metabolic syndromes, such as diabetes and obesity.
To drive progress in this new research area beyond the state-of-the-art it is proposed to: i) Elucidate the molecular mechanisms by which Activins regulate Ca2+ influx and insulin secretion in pancreatic ²-cells; ii) Elucidate the molecular mechanisms underlying the effects of GDF-3 on adipocyte metabolism, turnover and fat accumulation; iii) Investigate the interplay between insulin levels and fat deposition in the development of insulin resistance using mutant mice lacking Activin B and GDF-3; iv) Investigate tissue-specific contributions of ALK7 and ALK4 signaling to metabolic control by generating and characterizing conditional mutant mice; v) Investigate the effects of specific and reversible inactivation of ALK7 and ALK4 on metabolic regulation using a novel chemical-genetic approach based on analog-sensitive alleles.
This is research of a high-gain/high-risk nature. It is posed to open unique opportunities for further exploration of complex metabolic networks. The development of drugs capable of enhancing insulin secretion, limiting fat accumulation and ameliorating diet-induced obesity by targeting components of the ALK7 signaling network will find a strong rationale in the results of the proposed work.
Summary
The aim of this proposal is to understand a novel regulatory signaling network controlling insulin secretion, fat accumulation and energy balance centered around selected components of the TGF-² signaling system, including Activins A and B, GDF-3 and their receptors ALK7 and ALK4. Recent results from my laboratory indicate that these molecules are part of paracrine signaling networks that control important functions in pancreatic islets and adipose tissue through feedback inhibition and feed-forward regulation. These discoveries have open up a new research area with important implications for the understanding of metabolic networks and the treatment of human metabolic syndromes, such as diabetes and obesity.
To drive progress in this new research area beyond the state-of-the-art it is proposed to: i) Elucidate the molecular mechanisms by which Activins regulate Ca2+ influx and insulin secretion in pancreatic ²-cells; ii) Elucidate the molecular mechanisms underlying the effects of GDF-3 on adipocyte metabolism, turnover and fat accumulation; iii) Investigate the interplay between insulin levels and fat deposition in the development of insulin resistance using mutant mice lacking Activin B and GDF-3; iv) Investigate tissue-specific contributions of ALK7 and ALK4 signaling to metabolic control by generating and characterizing conditional mutant mice; v) Investigate the effects of specific and reversible inactivation of ALK7 and ALK4 on metabolic regulation using a novel chemical-genetic approach based on analog-sensitive alleles.
This is research of a high-gain/high-risk nature. It is posed to open unique opportunities for further exploration of complex metabolic networks. The development of drugs capable of enhancing insulin secretion, limiting fat accumulation and ameliorating diet-induced obesity by targeting components of the ALK7 signaling network will find a strong rationale in the results of the proposed work.
Max ERC Funding
2 462 154 €
Duration
Start date: 2009-04-01, End date: 2014-03-31
Project acronym ALMA
Project Attosecond Control of Light and Matter
Researcher (PI) Anne L'huillier
Host Institution (HI) LUNDS UNIVERSITET
Call Details Advanced Grant (AdG), PE2, ERC-2008-AdG
Summary Attosecond light pulses are generated when an intense laser interacts with a gas target. These pulses are not only short, enabling the study of electronic processes at their natural time scale, but also coherent. The vision of this proposal is to extend temporal coherent control concepts to a completely new regime of time and energy, combining (i) ultrashort pulses (ii) broadband excitation (iii) high photon energy, allowing scientists to reach not only valence but also inner shells in atoms and molecules, and, when needed, (iv) high spatial resolution. We want to explore how elementary electronic processes in atoms, molecules and more complex systems can be controlled by using well designed sequences of attosecond pulses. The research project proposed is organized into four parts: 1. Attosecond control of light leading to controlled sequences of attosecond pulses We will develop techniques to generate sequences of attosecond pulses with a variable number of pulses and controlled carrier-envelope-phase variation between consecutive pulses. 2. Attosecond control of electronic processes in atoms and molecules We will investigate the dynamics and coherence of phenomena induced by attosecond excitation of electron wave packets in various systems and we will explore how they can be controlled by a controlled sequence of ultrashort pulses. 3. Intense attosecond sources to reach the nonlinear regime We will optimize attosecond light sources in a systematic way, including amplification of the radiation by injecting a free electron laser. This will open up the possibility to develop nonlinear measurement and control schemes. 4. Attosecond control in more complex systems, including high spatial resolution We will develop ultrafast microscopy techniques, in order to obtain meaningful temporal information in surface and solid state physics. Two directions will be explored, digital in line microscopic holography and photoemission electron microscopy.
Summary
Attosecond light pulses are generated when an intense laser interacts with a gas target. These pulses are not only short, enabling the study of electronic processes at their natural time scale, but also coherent. The vision of this proposal is to extend temporal coherent control concepts to a completely new regime of time and energy, combining (i) ultrashort pulses (ii) broadband excitation (iii) high photon energy, allowing scientists to reach not only valence but also inner shells in atoms and molecules, and, when needed, (iv) high spatial resolution. We want to explore how elementary electronic processes in atoms, molecules and more complex systems can be controlled by using well designed sequences of attosecond pulses. The research project proposed is organized into four parts: 1. Attosecond control of light leading to controlled sequences of attosecond pulses We will develop techniques to generate sequences of attosecond pulses with a variable number of pulses and controlled carrier-envelope-phase variation between consecutive pulses. 2. Attosecond control of electronic processes in atoms and molecules We will investigate the dynamics and coherence of phenomena induced by attosecond excitation of electron wave packets in various systems and we will explore how they can be controlled by a controlled sequence of ultrashort pulses. 3. Intense attosecond sources to reach the nonlinear regime We will optimize attosecond light sources in a systematic way, including amplification of the radiation by injecting a free electron laser. This will open up the possibility to develop nonlinear measurement and control schemes. 4. Attosecond control in more complex systems, including high spatial resolution We will develop ultrafast microscopy techniques, in order to obtain meaningful temporal information in surface and solid state physics. Two directions will be explored, digital in line microscopic holography and photoemission electron microscopy.
Max ERC Funding
2 250 000 €
Duration
Start date: 2008-12-01, End date: 2013-11-30
Project acronym AMIMOS
Project Agile MIMO Systems for Communications, Biomedicine, and Defense
Researcher (PI) Bjorn Ottersten
Host Institution (HI) KUNGLIGA TEKNISKA HOEGSKOLAN
Call Details Advanced Grant (AdG), PE7, ERC-2008-AdG
Summary This proposal targets the emerging frontier research field of multiple-input multiple-output (MIMO) systems along with several innovative and somewhat unconventional applications of such systems. The use of arrays of transmitters and receivers will have a profound impact on future medical imaging/therapy systems, radar systems, and radio communication networks. Multiple transmitters provide a tremendous versatility and allow waveforms to be adapted temporally and spatially to environmental conditions. This is useful for individually tailored illumination of human tissue in biomedical imaging or ultrasound therapy. In radar systems, multiple transmit beams can be formed simultaneously via separate waveform designs allowing accurate target classification. In a wireless communication system, multiple communication signals can be directed to one or more users at the same time on the same frequency carrier. In addition, multiple receivers can be used in the above applications to provide increased detection performance, interference rejection, and improved estimation accuracy. The joint modelling, analysis, and design of these multidimensional transmit and receive schemes form the core of this research proposal. Ultimately, our research aims at developing the fundamental tools that will allow the design of wireless communication systems with an order-of-magnitude higher capacity at a lower cost than today; of ultrasound therapy systems maximizing delivered power while reducing treatment duration and unwanted illumination; and of distributed aperture multi-beam radars allowing more effective target location, identification, and classification. Europe has several successful industries that are active in biomedical imaging/therapy, radar systems, and wireless communications. The future success of these sectors critically depends on the ability to innovate and integrate new technology.
Summary
This proposal targets the emerging frontier research field of multiple-input multiple-output (MIMO) systems along with several innovative and somewhat unconventional applications of such systems. The use of arrays of transmitters and receivers will have a profound impact on future medical imaging/therapy systems, radar systems, and radio communication networks. Multiple transmitters provide a tremendous versatility and allow waveforms to be adapted temporally and spatially to environmental conditions. This is useful for individually tailored illumination of human tissue in biomedical imaging or ultrasound therapy. In radar systems, multiple transmit beams can be formed simultaneously via separate waveform designs allowing accurate target classification. In a wireless communication system, multiple communication signals can be directed to one or more users at the same time on the same frequency carrier. In addition, multiple receivers can be used in the above applications to provide increased detection performance, interference rejection, and improved estimation accuracy. The joint modelling, analysis, and design of these multidimensional transmit and receive schemes form the core of this research proposal. Ultimately, our research aims at developing the fundamental tools that will allow the design of wireless communication systems with an order-of-magnitude higher capacity at a lower cost than today; of ultrasound therapy systems maximizing delivered power while reducing treatment duration and unwanted illumination; and of distributed aperture multi-beam radars allowing more effective target location, identification, and classification. Europe has several successful industries that are active in biomedical imaging/therapy, radar systems, and wireless communications. The future success of these sectors critically depends on the ability to innovate and integrate new technology.
Max ERC Funding
1 872 720 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym ICEBERG
Project Discovery of Type 2 Diabetes Targets
Researcher (PI) Juleen Rae Zierath
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary This proposal is focused on the identification and biological validation of the metabolic pathways and key regulatory genes that control insulin sensitivity in Type 2 diabetes mellitus (T2DM). We are focusing on skeletal muscle because it is quantitatively the most important tissue involved in maintaining glucose homeostasis under insulin-stimulated conditions and it is a major site of insulin resistance in T2DM. Our central hypothesis is that alterations in insulin signal transduction to glucose transport contribute to the profound impairment in whole body glucose homeostasis and T2DM pathogenesis. Identification of the defects in T2DM can lead to the development of new therapeutic strategies to prevent and cure this disease. The proposal is divided into two main objectives: We will apply: 1) target identification platforms including microarray, proteomics and bioinformatics to identify dysregulated genes in normal glucose tolerant versus T2DM subjects or genetically modified model systems and 2) functional genomics to assign a physiological role of the identified targets in Aim 1 using cellular and whole-body approaches. We will focus on the mitogen-activated protein kinase family, the energy-sensing enzyme AMP-activated protein kinase, and the lipid intermediate metabolizing enzyme diacylglycerol kinase delta. Our previous work indicates that these candidates play a role in the regulation of glucose metabolism, triglyceride storage, and energy homeostasis.
Summary
This proposal is focused on the identification and biological validation of the metabolic pathways and key regulatory genes that control insulin sensitivity in Type 2 diabetes mellitus (T2DM). We are focusing on skeletal muscle because it is quantitatively the most important tissue involved in maintaining glucose homeostasis under insulin-stimulated conditions and it is a major site of insulin resistance in T2DM. Our central hypothesis is that alterations in insulin signal transduction to glucose transport contribute to the profound impairment in whole body glucose homeostasis and T2DM pathogenesis. Identification of the defects in T2DM can lead to the development of new therapeutic strategies to prevent and cure this disease. The proposal is divided into two main objectives: We will apply: 1) target identification platforms including microarray, proteomics and bioinformatics to identify dysregulated genes in normal glucose tolerant versus T2DM subjects or genetically modified model systems and 2) functional genomics to assign a physiological role of the identified targets in Aim 1 using cellular and whole-body approaches. We will focus on the mitogen-activated protein kinase family, the energy-sensing enzyme AMP-activated protein kinase, and the lipid intermediate metabolizing enzyme diacylglycerol kinase delta. Our previous work indicates that these candidates play a role in the regulation of glucose metabolism, triglyceride storage, and energy homeostasis.
Max ERC Funding
2 500 000 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym OSIRIS
Project Open silicon based research platform for emerging devices
Researcher (PI) Lars Mikael Östling
Host Institution (HI) KUNGLIGA TEKNISKA HOEGSKOLAN
Call Details Advanced Grant (AdG), PE7, ERC-2008-AdG
Summary The OSIRIS proposal will address the crucial and ultimately strategic area for the future emerging nanoelectronics, i.e. how structures and devices actually will be fabricated as physical dimensions approaches a few nanometer minimum feature size. The project title is Open silicon based research platform for emerging devices and indicates that many of the future emerging devices will be based on a silicon fabrication base platform but may not be fully based on silicon as the active semiconductor material. Over the past 10 years this research team has established a versatile fabrication technology platform in excellent condition to open up a variety of new technologies to explore nanometer minimum feature size in realizable electrical repeatable devices structures.
The proposed project has five different focus areas outlined. It covers a broad range of critical research issues that can be foreseen as groundbreaking topics for the period beyond 2015. the different topics addressed are;
1) Three dimensional FET nanostructures based on SiNW and GeNW with advanced configuration.
2) New applications of SiNW with build-in strain for fast silicon-base optoelectronic devices.
3) Low frequency noise in advanced nanoelectronic structures
4) THz devices for IR-detection
5) Bio-sensor nanoelectronics for extreme bio-molecule sensitivity and real time detection of DNA.
These areas are carefully chosen to assemble the right mix with predictable research success and with a few areas that can be called high gain/high risk. In particular we want to mention that focus area 2 and 4 have a great potential impact when successful but also at a certain higher risk for a more difficult implementation in future devices. There is in no cases any risk that the research will not generate high quality scientific results.
Summary
The OSIRIS proposal will address the crucial and ultimately strategic area for the future emerging nanoelectronics, i.e. how structures and devices actually will be fabricated as physical dimensions approaches a few nanometer minimum feature size. The project title is Open silicon based research platform for emerging devices and indicates that many of the future emerging devices will be based on a silicon fabrication base platform but may not be fully based on silicon as the active semiconductor material. Over the past 10 years this research team has established a versatile fabrication technology platform in excellent condition to open up a variety of new technologies to explore nanometer minimum feature size in realizable electrical repeatable devices structures.
The proposed project has five different focus areas outlined. It covers a broad range of critical research issues that can be foreseen as groundbreaking topics for the period beyond 2015. the different topics addressed are;
1) Three dimensional FET nanostructures based on SiNW and GeNW with advanced configuration.
2) New applications of SiNW with build-in strain for fast silicon-base optoelectronic devices.
3) Low frequency noise in advanced nanoelectronic structures
4) THz devices for IR-detection
5) Bio-sensor nanoelectronics for extreme bio-molecule sensitivity and real time detection of DNA.
These areas are carefully chosen to assemble the right mix with predictable research success and with a few areas that can be called high gain/high risk. In particular we want to mention that focus area 2 and 4 have a great potential impact when successful but also at a certain higher risk for a more difficult implementation in future devices. There is in no cases any risk that the research will not generate high quality scientific results.
Max ERC Funding
1 999 500 €
Duration
Start date: 2009-06-01, End date: 2014-05-31
Project acronym STEMRENEWAL
Project Identification of a new mechanism of stem cell self-renewal; direct implications on self-repair and tumor initiating cells in the brain
Researcher (PI) Patrik Ernfors
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary The self-renewing nature of stem cells is a consequence of their ability to proliferate indefinitely while maintaining pluripotency. Mechanisms of pluripotency are well known but mechanisms controlling stem cell proliferation are unknown. Proliferation of somatic cells takes place in G1 cell cycle phase. We have identified that embryonic and peripheral neural stem cell proliferation is regulated by an entirely new mechanism involving chromatin remodeling and operating in the S/G2 phase of the cell cycle (Andang et al., Nature 2009). This involves the DNA damage response (DDR) pathway proteins. The DDR pathway is activated physiologically by GABA acting by the GABAA receptor leading to Cl- influx, cell swelling, and by unknown mechanism, activation of the PI3K related kinases ATR/ATM which phosphorylates histone H2AX. Combined, the data suggests that the DDR pathway is operating in a ligand-dependent manner under normal physiological conditions and that it may serve as a new molecular mechanism regulating cell proliferation in eukaryotic cells. We propose a homeostatic mechanism of stem cell proliferation where negative feedback control of the cell cycle adjusts stem cell numbers. The demonstration of normal, physiological, ligand-induced activation of these pathways in stem cell niches opens fundamentally new insight into the mechanisms of stem cell proliferation and surveillance against cancer. Once characterized, we propose that these mechanisms may be exploited to induce self repair following brain damage and to manipulate cell survival in tumor initiating cells of the brain (that share many characteristics with stem cells). The potential benefit of this proposed research could be vast, involving potentially a unifying mechanism how all stem cell niches in the embryo and in the adult individual is regulated and can be manipulated.
Summary
The self-renewing nature of stem cells is a consequence of their ability to proliferate indefinitely while maintaining pluripotency. Mechanisms of pluripotency are well known but mechanisms controlling stem cell proliferation are unknown. Proliferation of somatic cells takes place in G1 cell cycle phase. We have identified that embryonic and peripheral neural stem cell proliferation is regulated by an entirely new mechanism involving chromatin remodeling and operating in the S/G2 phase of the cell cycle (Andang et al., Nature 2009). This involves the DNA damage response (DDR) pathway proteins. The DDR pathway is activated physiologically by GABA acting by the GABAA receptor leading to Cl- influx, cell swelling, and by unknown mechanism, activation of the PI3K related kinases ATR/ATM which phosphorylates histone H2AX. Combined, the data suggests that the DDR pathway is operating in a ligand-dependent manner under normal physiological conditions and that it may serve as a new molecular mechanism regulating cell proliferation in eukaryotic cells. We propose a homeostatic mechanism of stem cell proliferation where negative feedback control of the cell cycle adjusts stem cell numbers. The demonstration of normal, physiological, ligand-induced activation of these pathways in stem cell niches opens fundamentally new insight into the mechanisms of stem cell proliferation and surveillance against cancer. Once characterized, we propose that these mechanisms may be exploited to induce self repair following brain damage and to manipulate cell survival in tumor initiating cells of the brain (that share many characteristics with stem cells). The potential benefit of this proposed research could be vast, involving potentially a unifying mechanism how all stem cell niches in the embryo and in the adult individual is regulated and can be manipulated.
Max ERC Funding
2 492 593 €
Duration
Start date: 2009-03-01, End date: 2014-02-28
