Project acronym 3D-OA-HISTO
Project Development of 3D Histopathological Grading of Osteoarthritis
Researcher (PI) Simo Jaakko Saarakkala
Host Institution (HI) OULUN YLIOPISTO
Call Details Starting Grant (StG), LS7, ERC-2013-StG
Summary "Background: Osteoarthritis (OA) is a common musculoskeletal disease occurring worldwide. Despite extensive research, etiology of OA is still poorly understood. Histopathological grading (HPG) of 2D tissue sections is the gold standard reference method for determination of OA stage. However, traditional 2D-HPG is destructive and based only on subjective visual evaluation. These limitations induce bias to clinical in vitro OA diagnostics and basic research that both rely strongly on HPG.
Objectives: 1) To establish and validate the very first 3D-HPG of OA based on cutting-edge nano/micro-CT (Computed Tomography) technologies in vitro; 2) To use the established method to clarify the beginning phases of OA; and 3) To validate 3D-HPG of OA for in vivo use.
Methods: Several hundreds of human osteochondral samples from patients undergoing total knee arthroplasty will be collected. The samples will be imaged in vitro with nano/micro-CT and clinical high-end extremity CT devices using specific contrast-agents to quantify tissue constituents and structure in 3D in large volume. From this information, a novel 3D-HPG is developed with statistical classification algorithms. Finally, the developed novel 3D-HPG of OA will be applied clinically in vivo.
Significance: This is the very first study to establish 3D-HPG of OA pathology in vitro and in vivo. Furthermore, the developed technique hugely improves the understanding of the beginning phases of OA. Ultimately, the study will contribute for improving OA patients’ quality of life by slowing the disease progression, and for providing powerful tools to develop new OA therapies."
Summary
"Background: Osteoarthritis (OA) is a common musculoskeletal disease occurring worldwide. Despite extensive research, etiology of OA is still poorly understood. Histopathological grading (HPG) of 2D tissue sections is the gold standard reference method for determination of OA stage. However, traditional 2D-HPG is destructive and based only on subjective visual evaluation. These limitations induce bias to clinical in vitro OA diagnostics and basic research that both rely strongly on HPG.
Objectives: 1) To establish and validate the very first 3D-HPG of OA based on cutting-edge nano/micro-CT (Computed Tomography) technologies in vitro; 2) To use the established method to clarify the beginning phases of OA; and 3) To validate 3D-HPG of OA for in vivo use.
Methods: Several hundreds of human osteochondral samples from patients undergoing total knee arthroplasty will be collected. The samples will be imaged in vitro with nano/micro-CT and clinical high-end extremity CT devices using specific contrast-agents to quantify tissue constituents and structure in 3D in large volume. From this information, a novel 3D-HPG is developed with statistical classification algorithms. Finally, the developed novel 3D-HPG of OA will be applied clinically in vivo.
Significance: This is the very first study to establish 3D-HPG of OA pathology in vitro and in vivo. Furthermore, the developed technique hugely improves the understanding of the beginning phases of OA. Ultimately, the study will contribute for improving OA patients’ quality of life by slowing the disease progression, and for providing powerful tools to develop new OA therapies."
Max ERC Funding
1 500 000 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym AAREA
Project The Archaeology of Agricultural Resilience in Eastern Africa
Researcher (PI) Daryl Stump
Host Institution (HI) UNIVERSITY OF YORK
Call Details Starting Grant (StG), SH6, ERC-2013-StG
Summary "The twin concepts of sustainability and conservation that are so pivotal within current debates regarding economic development and biodiversity protection both contain an inherent temporal dimension, since both refer to the need to balance short-term gains with long-term resource maintenance. Proponents of resilience theory and of development based on ‘indigenous knowledge’ have thus argued for the necessity of including archaeological, historical and palaeoenvironmental components within development project design. Indeed, some have argued that archaeology should lead these interdisciplinary projects on the grounds that it provides the necessary time depth and bridges the social and natural sciences. The project proposed here accepts this logic and endorses this renewed contemporary relevance of archaeological research. However, it also needs to be admitted that moving beyond critiques of the misuse of historical data presents significant hurdles. When presenting results outside the discipline, for example, archaeological projects tend to downplay the poor archaeological visibility of certain agricultural practices, and computer models designed to test sustainability struggle to adequately account for local cultural preferences. This field will therefore not progress unless there is a frank appraisal of archaeology’s strengths and weaknesses. This project will provide this assessment by employing a range of established and groundbreaking archaeological and modelling techniques to examine the development of two east Africa agricultural systems: one at the abandoned site of Engaruka in Tanzania, commonly seen as an example of resource mismanagement and ecological collapse; and another at the current agricultural landscape in Konso, Ethiopia, described by the UN FAO as one of a select few African “lessons from the past”. The project thus aims to assess the sustainability of these systems, but will also assess the role archaeology can play in such debates worldwide."
Summary
"The twin concepts of sustainability and conservation that are so pivotal within current debates regarding economic development and biodiversity protection both contain an inherent temporal dimension, since both refer to the need to balance short-term gains with long-term resource maintenance. Proponents of resilience theory and of development based on ‘indigenous knowledge’ have thus argued for the necessity of including archaeological, historical and palaeoenvironmental components within development project design. Indeed, some have argued that archaeology should lead these interdisciplinary projects on the grounds that it provides the necessary time depth and bridges the social and natural sciences. The project proposed here accepts this logic and endorses this renewed contemporary relevance of archaeological research. However, it also needs to be admitted that moving beyond critiques of the misuse of historical data presents significant hurdles. When presenting results outside the discipline, for example, archaeological projects tend to downplay the poor archaeological visibility of certain agricultural practices, and computer models designed to test sustainability struggle to adequately account for local cultural preferences. This field will therefore not progress unless there is a frank appraisal of archaeology’s strengths and weaknesses. This project will provide this assessment by employing a range of established and groundbreaking archaeological and modelling techniques to examine the development of two east Africa agricultural systems: one at the abandoned site of Engaruka in Tanzania, commonly seen as an example of resource mismanagement and ecological collapse; and another at the current agricultural landscape in Konso, Ethiopia, described by the UN FAO as one of a select few African “lessons from the past”. The project thus aims to assess the sustainability of these systems, but will also assess the role archaeology can play in such debates worldwide."
Max ERC Funding
1 196 701 €
Duration
Start date: 2014-02-01, End date: 2018-01-31
Project acronym AGESPACE
Project SPATIAL NAVIGATION – A UNIQUE WINDOW INTO MECHANISMS OF COGNITIVE AGEING
Researcher (PI) Thomas Wolbers
Host Institution (HI) DEUTSCHES ZENTRUM FUR NEURODEGENERATIVE ERKRANKUNGEN EV
Call Details Starting Grant (StG), SH4, ERC-2013-StG
Summary "By 2040, the European population aged over 60 will rise to 290 million, with those estimated to have dementia to 15.9 million. These dramatic demographic changes will pose huge challenges to health care systems, hence a detailed understanding of age-related cognitive and neurobiological changes is essential for helping elderly populations maintain independence. However, while existing research into cognitive ageing has carefully characterised developmental trajectories of functions such as memory and processing speed, one key cognitive ability that is particularly relevant to everyday functioning has received very little attention: In surveys, elderly people often report substantial declines in navigational abilities such as problems with finding one’s way in a novel environment. Such deficits severely restrict the mobility of elderly people and affect physical activity and social participation, but the underlying behavioural and neuronal mechanisms are poorly understood.
In this proposal, I will take a new approach to cognitive ageing that will bridge the gap between animal neurobiology and human cognitive neuroscience. With support from the ERC, I will create a team that will characterise the mechanisms mediating age-related changes in navigational processing in humans. The project will focus on three structures that perform key computations for spatial navigation, form a closely interconnected triadic network, and are particularly sensitive to the ageing process. Crucially, the team will employ an interdisciplinary methodological approach that combines mathematical modelling, brain imaging and innovative data analysis techniques with novel virtual environment technology, which allows for rigorous testing of predictions derived from animal findings. Finally, the proposal also incorporates a translational project aimed at improving spatial mnemonic functioning with a behavioural intervention, which provides a direct test of functional relevance and societal impact."
Summary
"By 2040, the European population aged over 60 will rise to 290 million, with those estimated to have dementia to 15.9 million. These dramatic demographic changes will pose huge challenges to health care systems, hence a detailed understanding of age-related cognitive and neurobiological changes is essential for helping elderly populations maintain independence. However, while existing research into cognitive ageing has carefully characterised developmental trajectories of functions such as memory and processing speed, one key cognitive ability that is particularly relevant to everyday functioning has received very little attention: In surveys, elderly people often report substantial declines in navigational abilities such as problems with finding one’s way in a novel environment. Such deficits severely restrict the mobility of elderly people and affect physical activity and social participation, but the underlying behavioural and neuronal mechanisms are poorly understood.
In this proposal, I will take a new approach to cognitive ageing that will bridge the gap between animal neurobiology and human cognitive neuroscience. With support from the ERC, I will create a team that will characterise the mechanisms mediating age-related changes in navigational processing in humans. The project will focus on three structures that perform key computations for spatial navigation, form a closely interconnected triadic network, and are particularly sensitive to the ageing process. Crucially, the team will employ an interdisciplinary methodological approach that combines mathematical modelling, brain imaging and innovative data analysis techniques with novel virtual environment technology, which allows for rigorous testing of predictions derived from animal findings. Finally, the proposal also incorporates a translational project aimed at improving spatial mnemonic functioning with a behavioural intervention, which provides a direct test of functional relevance and societal impact."
Max ERC Funding
1 318 990 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym APPLAUSE
Project Adolescent Precursors to Psychiatric Disorders – Learing from Analysis of User-Service Engagement
Researcher (PI) Sara Evans
Host Institution (HI) LONDON SCHOOL OF ECONOMICS AND POLITICAL SCIENCE
Call Details Starting Grant (StG), LS7, ERC-2013-StG
Summary APPLAUSE’s aim is to produce a body of evidence that illustrates how young people with mental health problems currently interact with both formal mental health services and informal social and familial support structures. Careful analysis of data gathered in the UK and Brazil will allow formulation of globally relevant insights into mental health care delivery for young people, which will be presented internationally as a resource for future health care service design.
APPLAUSE will allow the collection of an important data set that does not currently exist in this field, and will look to other disciplines for innovative approaches to data analysis. Whist standard analysis may allow for snapshots of health service use, using innovative life course methods will allow us to to characterise patterns of complete service use of each individual participant’s experience of accessing mental health care and social support.
Adolescence is a critical period in mental health development, which has been largely neglected by public health efforts. Psychiatric disorders rank as the primary cause of disability among individuals aged 10-24 years, worldwide. Moreover, many health risk behaviours emerge during adolescence and 70% of adult psychiatric disorders are preceded by mental health problems during adolescent years. However, delays to receiving care for psychiatric disorders, following disorder onset, avreage more than ten years and little is known about factors which impede access to and continuity of care among young people with mental health problems. APPLAUSE will analyse current access models, reports of individual experiences of positive and negative interactions with health care services and the culturally embedded social factors that impact on such access. Addressing this complex problem from a global perspective will advance the development of a more diverse and innovative set of strategies for improving earlier access to care.
Summary
APPLAUSE’s aim is to produce a body of evidence that illustrates how young people with mental health problems currently interact with both formal mental health services and informal social and familial support structures. Careful analysis of data gathered in the UK and Brazil will allow formulation of globally relevant insights into mental health care delivery for young people, which will be presented internationally as a resource for future health care service design.
APPLAUSE will allow the collection of an important data set that does not currently exist in this field, and will look to other disciplines for innovative approaches to data analysis. Whist standard analysis may allow for snapshots of health service use, using innovative life course methods will allow us to to characterise patterns of complete service use of each individual participant’s experience of accessing mental health care and social support.
Adolescence is a critical period in mental health development, which has been largely neglected by public health efforts. Psychiatric disorders rank as the primary cause of disability among individuals aged 10-24 years, worldwide. Moreover, many health risk behaviours emerge during adolescence and 70% of adult psychiatric disorders are preceded by mental health problems during adolescent years. However, delays to receiving care for psychiatric disorders, following disorder onset, avreage more than ten years and little is known about factors which impede access to and continuity of care among young people with mental health problems. APPLAUSE will analyse current access models, reports of individual experiences of positive and negative interactions with health care services and the culturally embedded social factors that impact on such access. Addressing this complex problem from a global perspective will advance the development of a more diverse and innovative set of strategies for improving earlier access to care.
Max ERC Funding
1 499 948 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym BETTERSENSE
Project Nanodevice Engineering for a Better Chemical Gas Sensing Technology
Researcher (PI) Juan Daniel Prades Garcia
Host Institution (HI) UNIVERSITAT DE BARCELONA
Call Details Starting Grant (StG), PE7, ERC-2013-StG
Summary BetterSense aims to solve the two main problems in current gas sensor technologies: the high power consumption and the poor selectivity. For the former, we propose a radically new approach: to integrate the sensing components and the energy sources intimately, at the nanoscale, in order to achieve a new kind of sensor concept featuring zero power consumption. For the latter, we will mimic the biological receptors designing a kit of gas-specific molecular organic functionalizations to reach ultra-high gas selectivity figures, comparable to those of biological processes. Both cutting-edge concepts will be developed in parallel an integrated together to render a totally new gas sensing technology that surpasses the state-of-the-art.
As a matter of fact, the project will enable, for the first time, the integration of gas detectors in energetically autonomous sensors networks. Additionally, BetterSense will provide an integral solution to the gas sensing challenge by producing a full set of gas-specific sensors over the same platform to ease their integration in multi-analyte systems. Moreover, the project approach will certainly open opportunities in adjacent fields in which power consumption, specificity and nano/micro integration are a concern, such as liquid chemical and biological sensing.
In spite of the promising evidences that demonstrate the feasibility of this proposal, there are still many scientific and technological issues to solve, most of them in the edge of what is known and what is possible today in nano-fabrication and nano/micro integration. For this reason, BetterSense also aims to contribute to the global challenge of making nanodevices compatible with scalable, cost-effective, microelectronic technologies.
For all this, addressing this challenging proposal in full requires a funding scheme compatible with a high-risk/high-gain vision to finance the full dedication of a highly motivated research team with multidisciplinary skill
Summary
BetterSense aims to solve the two main problems in current gas sensor technologies: the high power consumption and the poor selectivity. For the former, we propose a radically new approach: to integrate the sensing components and the energy sources intimately, at the nanoscale, in order to achieve a new kind of sensor concept featuring zero power consumption. For the latter, we will mimic the biological receptors designing a kit of gas-specific molecular organic functionalizations to reach ultra-high gas selectivity figures, comparable to those of biological processes. Both cutting-edge concepts will be developed in parallel an integrated together to render a totally new gas sensing technology that surpasses the state-of-the-art.
As a matter of fact, the project will enable, for the first time, the integration of gas detectors in energetically autonomous sensors networks. Additionally, BetterSense will provide an integral solution to the gas sensing challenge by producing a full set of gas-specific sensors over the same platform to ease their integration in multi-analyte systems. Moreover, the project approach will certainly open opportunities in adjacent fields in which power consumption, specificity and nano/micro integration are a concern, such as liquid chemical and biological sensing.
In spite of the promising evidences that demonstrate the feasibility of this proposal, there are still many scientific and technological issues to solve, most of them in the edge of what is known and what is possible today in nano-fabrication and nano/micro integration. For this reason, BetterSense also aims to contribute to the global challenge of making nanodevices compatible with scalable, cost-effective, microelectronic technologies.
For all this, addressing this challenging proposal in full requires a funding scheme compatible with a high-risk/high-gain vision to finance the full dedication of a highly motivated research team with multidisciplinary skill
Max ERC Funding
1 498 452 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym BIO-IRT
Project Biologically individualized, model-based radiotherapy on the basis of multi-parametric molecular tumour profiling
Researcher (PI) Daniela Thorwarth
Host Institution (HI) EBERHARD KARLS UNIVERSITAET TUEBINGEN
Call Details Starting Grant (StG), LS7, ERC-2013-StG
Summary High precision radiotherapy (RT) allows extremely flexible tumour treatments achieving highly conformal radiation doses while sparing surrounding organs at risk. Nevertheless, failure rates of up to 50% are reported for head and neck cancer (HNC) due to radiation resistance induced by pathophysiologic factors such as hypoxia and other clinical factors as HPV-status, stage and tumour volume.
This project aims at developing a multi-parametric model for individualized RT (iRT) dose prescriptions in HNC based on biological markers and functional PET/MR imaging. This project goes far beyond current research standards and clinical practice as it aims for establishing hypoxia PET and f-MRI as well as biological markers in HNC as a role model for a novel concept from anatomy-based to biologically iRT.
During this project, a multi-parametric model will be developed on a preclinical basis that combines biological markers such as different oncogenes and hypoxia gene classifier with functional PET/MR imaging, such as FMISO PET in combination with different f-MRI techniques, like DW-, DCE- and BOLD-MRI in addition to MR spectroscopy. The ultimate goal of this project is a multi-parametric model to predict therapy outcome and guide iRT.
In a second part, a clinical study will be carried out to validate the preclinical model in patients. Based on the most informative radiobiological and imaging parameters as identified during the pre-clinical phase, biological markers and advanced PET/MR imaging will be evaluated in terms of their potential for iRT dose prescription.
Successful development of a model for biologically iRT prescription on the basis of multi-parametric molecular profiling would provide a unique basis for personalized cancer treatment. A validated multi-parametric model for RT outcome would represent a paradigm shift from anatomy-based to biologically iRT concepts with the ultimate goal of improving cancer cure rates.
Summary
High precision radiotherapy (RT) allows extremely flexible tumour treatments achieving highly conformal radiation doses while sparing surrounding organs at risk. Nevertheless, failure rates of up to 50% are reported for head and neck cancer (HNC) due to radiation resistance induced by pathophysiologic factors such as hypoxia and other clinical factors as HPV-status, stage and tumour volume.
This project aims at developing a multi-parametric model for individualized RT (iRT) dose prescriptions in HNC based on biological markers and functional PET/MR imaging. This project goes far beyond current research standards and clinical practice as it aims for establishing hypoxia PET and f-MRI as well as biological markers in HNC as a role model for a novel concept from anatomy-based to biologically iRT.
During this project, a multi-parametric model will be developed on a preclinical basis that combines biological markers such as different oncogenes and hypoxia gene classifier with functional PET/MR imaging, such as FMISO PET in combination with different f-MRI techniques, like DW-, DCE- and BOLD-MRI in addition to MR spectroscopy. The ultimate goal of this project is a multi-parametric model to predict therapy outcome and guide iRT.
In a second part, a clinical study will be carried out to validate the preclinical model in patients. Based on the most informative radiobiological and imaging parameters as identified during the pre-clinical phase, biological markers and advanced PET/MR imaging will be evaluated in terms of their potential for iRT dose prescription.
Successful development of a model for biologically iRT prescription on the basis of multi-parametric molecular profiling would provide a unique basis for personalized cancer treatment. A validated multi-parametric model for RT outcome would represent a paradigm shift from anatomy-based to biologically iRT concepts with the ultimate goal of improving cancer cure rates.
Max ERC Funding
1 370 799 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym BioWater
Project Development of new chemical imaging techniques to understand the function of water in biocompatibility, biodegradation and biofouling
Researcher (PI) Aoife Ann Gowen
Host Institution (HI) UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN
Call Details Starting Grant (StG), PE8, ERC-2013-StG
Summary Water is the first molecule to come into contact with biomaterials in biological systems and thus essential to the processes of biodegradation, biocompatibility and biofouling. Despite this fact, little is currently known about how biomaterials interact with water. This knowledge is crucial for the development and optimisation of novel functional biomaterials for human health (e.g. biosensing devices, erodible biomaterials, drug release carriers, wound dressings). BioWater will develop near and mid infrared chemical imaging (NIR-MIR-CI) techniques to investigate the fundamental interaction between biomaterials and water in order to understand the key processes of biodegradation, biocompatibility and biofouling. This ambitious yet achievable project will focus on two major categories of biomaterials relevant to human health: extracellular collagens and synthetic biopolymers. Initially, interactions between these biomaterials and water will be investigated; subsequently interactions with more complicated matrices (e.g. protein solutions and cellular systems) will be studied. CI data will be correlated with standard surface characterization, biocompatibility and biodegradation measurements. Molecular dynamic simulations will complement this work to identify the most probable molecular structures of water at different biomaterial interfaces.
Advanced understanding of the role of water in biocompatibility, biofouling and biodegradation processes will facilitate the optimization of biomaterials tailored to specific cellular environments with a broad range of therapeutic applications (e.g. drug eluting stents, tissue engineering, wound healing). The new NIR-MIR-CI/chemometric methodologies developed in BioWater will allow for the rapid characterization and monitoring of novel biomaterials at pre-clinical stages, improving process control by overcoming the laborious and time consuming large-scale sampling methods currently required in biomaterials development.
Summary
Water is the first molecule to come into contact with biomaterials in biological systems and thus essential to the processes of biodegradation, biocompatibility and biofouling. Despite this fact, little is currently known about how biomaterials interact with water. This knowledge is crucial for the development and optimisation of novel functional biomaterials for human health (e.g. biosensing devices, erodible biomaterials, drug release carriers, wound dressings). BioWater will develop near and mid infrared chemical imaging (NIR-MIR-CI) techniques to investigate the fundamental interaction between biomaterials and water in order to understand the key processes of biodegradation, biocompatibility and biofouling. This ambitious yet achievable project will focus on two major categories of biomaterials relevant to human health: extracellular collagens and synthetic biopolymers. Initially, interactions between these biomaterials and water will be investigated; subsequently interactions with more complicated matrices (e.g. protein solutions and cellular systems) will be studied. CI data will be correlated with standard surface characterization, biocompatibility and biodegradation measurements. Molecular dynamic simulations will complement this work to identify the most probable molecular structures of water at different biomaterial interfaces.
Advanced understanding of the role of water in biocompatibility, biofouling and biodegradation processes will facilitate the optimization of biomaterials tailored to specific cellular environments with a broad range of therapeutic applications (e.g. drug eluting stents, tissue engineering, wound healing). The new NIR-MIR-CI/chemometric methodologies developed in BioWater will allow for the rapid characterization and monitoring of novel biomaterials at pre-clinical stages, improving process control by overcoming the laborious and time consuming large-scale sampling methods currently required in biomaterials development.
Max ERC Funding
1 487 682 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym BisProt
Project Developing Multispecific Biological Agents that Target Tumor Neovasculature for Cancer Imaging and Therapy
Researcher (PI) Niv Papo
Host Institution (HI) BEN-GURION UNIVERSITY OF THE NEGEV
Call Details Starting Grant (StG), LS7, ERC-2013-StG
Summary The dysregulation of signaling pathways that mediate cell proliferation, survival and migration is an underlying cause of many cancers. In particular, dysregulation and over-expression of avb3 integrin, membrane-type-1 matrix metalloproteinase (MT1-MMP; also known as matrix metalloproteinase-14, MMP14) and vascular endothelial growth factor receptor-2 (VEGFR2) correlate with poor prognosis in many human tumors, making these proteins attractive targets for therapeutic intervention. Numerous papers have demonstrated the cross-talk between biological processes mediated by αvβ3 integrins, MT1-MMP, VEGFR2, and their ligands, particularly pathways responsible for angiogenesis. Dual-specific proteins that can target and inhibit the activity of the above multiple receptors therefore have superior potential to single-targeted agents due to differential expression of these disease markers in different patients and the ability of this expression to change over time. Most currently available bispecific protein therapeutics comprise antibodies (Abs) or antibody fragments. The new approach proposed here entails rational and combinatorial methods for engineering multispecificity into small peptides and natural protein ligands to function as non-immunoglobulin alternatives to antibodies. In this innovative approach to creating dual-specific proteins, an additional functionality is introduced into a small peptide or into a natural protein ligand to complement its existing biological properties. We predict that this approach will form a major part of a highly effective strategy for creating ligand-based multispecific receptor inhibitors and molecular tools for protein recognition. We envision that protein variants generated from these efforts will promote the next generation of therapeutics including, but not limited to, molecular imaging agents, targeted drug delivery agents, and selective tissue targeting probes.
Summary
The dysregulation of signaling pathways that mediate cell proliferation, survival and migration is an underlying cause of many cancers. In particular, dysregulation and over-expression of avb3 integrin, membrane-type-1 matrix metalloproteinase (MT1-MMP; also known as matrix metalloproteinase-14, MMP14) and vascular endothelial growth factor receptor-2 (VEGFR2) correlate with poor prognosis in many human tumors, making these proteins attractive targets for therapeutic intervention. Numerous papers have demonstrated the cross-talk between biological processes mediated by αvβ3 integrins, MT1-MMP, VEGFR2, and their ligands, particularly pathways responsible for angiogenesis. Dual-specific proteins that can target and inhibit the activity of the above multiple receptors therefore have superior potential to single-targeted agents due to differential expression of these disease markers in different patients and the ability of this expression to change over time. Most currently available bispecific protein therapeutics comprise antibodies (Abs) or antibody fragments. The new approach proposed here entails rational and combinatorial methods for engineering multispecificity into small peptides and natural protein ligands to function as non-immunoglobulin alternatives to antibodies. In this innovative approach to creating dual-specific proteins, an additional functionality is introduced into a small peptide or into a natural protein ligand to complement its existing biological properties. We predict that this approach will form a major part of a highly effective strategy for creating ligand-based multispecific receptor inhibitors and molecular tools for protein recognition. We envision that protein variants generated from these efforts will promote the next generation of therapeutics including, but not limited to, molecular imaging agents, targeted drug delivery agents, and selective tissue targeting probes.
Max ERC Funding
1 625 000 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym BODYBUILDING
Project Building body representations: An investigation of the formation and maintenance of body representations
Researcher (PI) Matthew Ryan Longo
Host Institution (HI) BIRKBECK COLLEGE - UNIVERSITY OF LONDON
Call Details Starting Grant (StG), SH4, ERC-2013-StG
Summary "The body is ubiquitous in perceptual experience and is central to our sense of self and personal identity. Disordered body representations are central to several serious psychiatric and neurological disorders. Thus, identifying factors which contribute to the formation and maintenance of body representations is crucial for understanding how body representation goes awry in disease, and how it might be corrected by potential novel therapeutic interventions. Several types of sensory signals provide information about the body, making the body the multisensory object, par excellence. Little is known, however, about how information from somatosensation and from vision is integrated to construct the rich body representations we all experience. This project fills this gap in current understanding by determining how the brain builds body representations (BODYBUILDING). A hierarchical model of body representation is proposed, providing a novel theoretical framework for understanding the diversity of body representations and how they interact. The key motivating hypothesis is that body representation is determined by the dialectic between two major cognitive processes. First, from the bottom-up, somatosensation represents the body surface as a mosaic of discrete receptive fields, which become progressively agglomerated into larger and larger units of organisation, a process I call fusion. Second, from the top-down, vision starts out depicting the body as an undifferentiated whole, which is progressively broken into smaller parts, a process I call segmentation. Thus, body representation operates from the bottom-up as a process of fusion of primitive elements into larger complexes, as well as from the top-down as a process of segmentation of an initially undifferentiated whole into more basic parts. This project uses a combination of psychophysical, electrophysiological, and neuroimaging methods to provide fundamental insight into how we come to represent our body."
Summary
"The body is ubiquitous in perceptual experience and is central to our sense of self and personal identity. Disordered body representations are central to several serious psychiatric and neurological disorders. Thus, identifying factors which contribute to the formation and maintenance of body representations is crucial for understanding how body representation goes awry in disease, and how it might be corrected by potential novel therapeutic interventions. Several types of sensory signals provide information about the body, making the body the multisensory object, par excellence. Little is known, however, about how information from somatosensation and from vision is integrated to construct the rich body representations we all experience. This project fills this gap in current understanding by determining how the brain builds body representations (BODYBUILDING). A hierarchical model of body representation is proposed, providing a novel theoretical framework for understanding the diversity of body representations and how they interact. The key motivating hypothesis is that body representation is determined by the dialectic between two major cognitive processes. First, from the bottom-up, somatosensation represents the body surface as a mosaic of discrete receptive fields, which become progressively agglomerated into larger and larger units of organisation, a process I call fusion. Second, from the top-down, vision starts out depicting the body as an undifferentiated whole, which is progressively broken into smaller parts, a process I call segmentation. Thus, body representation operates from the bottom-up as a process of fusion of primitive elements into larger complexes, as well as from the top-down as a process of segmentation of an initially undifferentiated whole into more basic parts. This project uses a combination of psychophysical, electrophysiological, and neuroimaging methods to provide fundamental insight into how we come to represent our body."
Max ERC Funding
1 497 715 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym BRAINIMAGES
Project "How do we keep apart internally generated mental images from externally induced percepts? Dissociating mental imagery, working memory and conscious perception."
Researcher (PI) Juha Tapani Silvanto
Host Institution (HI) THE UNIVERSITY OF WESTMINSTER LBG
Call Details Starting Grant (StG), SH4, ERC-2013-StG
Summary "Conscious experiences normally result from the flow of external input into our sensory systems. However, our minds are also able to create conscious percepts in the absence of any sensory stimulation; these internally generated percepts are referred to as mental images, and they have many similarities with real visual percepts; consequently, mental imagery is often referred to as “seeing in the mind’s eye”. Mental imagery is also believed to be closely related to working memory, a mechanism which can maintain “offline” representations of visual stimuli no longer in the observer’s view, as both involve internal representations of previously seen visual attributes. Indeed, visual imagery is often thought of as a conscious window into the content of memory representations. Imagery, working memory, and conscious perception are thus thought to rely on very similar mechanisms. However, in everyday life we are generally able to keep apart the constructs of our imagination from real physical events; this begs the question of how the brain distinguishes internal mental images from externally induced visual percepts. To answer this question, the proposed work aims to isolate the cortical mechanisms associated uniquely with WM and imagery independently of each other and independently of the influence of external conscious percepts. Furthermore, by the use of neuroimaging and brain stimulation, we aim to determine the cortical mechanisms which keep apart internally generated and externally induced percepts, in both health and disease. This is a question of great clinical interest, as the ability to distinguish the perceived from the imagined is impoverished in psychotic disorders. In addition to revealing the mechanisms underlying this confusion, the present project aims to alleviate it in psychotic patients by the use of brain stimulation. The project will thus significantly improve our understanding of these cognitive processes and will also have clinical implications."
Summary
"Conscious experiences normally result from the flow of external input into our sensory systems. However, our minds are also able to create conscious percepts in the absence of any sensory stimulation; these internally generated percepts are referred to as mental images, and they have many similarities with real visual percepts; consequently, mental imagery is often referred to as “seeing in the mind’s eye”. Mental imagery is also believed to be closely related to working memory, a mechanism which can maintain “offline” representations of visual stimuli no longer in the observer’s view, as both involve internal representations of previously seen visual attributes. Indeed, visual imagery is often thought of as a conscious window into the content of memory representations. Imagery, working memory, and conscious perception are thus thought to rely on very similar mechanisms. However, in everyday life we are generally able to keep apart the constructs of our imagination from real physical events; this begs the question of how the brain distinguishes internal mental images from externally induced visual percepts. To answer this question, the proposed work aims to isolate the cortical mechanisms associated uniquely with WM and imagery independently of each other and independently of the influence of external conscious percepts. Furthermore, by the use of neuroimaging and brain stimulation, we aim to determine the cortical mechanisms which keep apart internally generated and externally induced percepts, in both health and disease. This is a question of great clinical interest, as the ability to distinguish the perceived from the imagined is impoverished in psychotic disorders. In addition to revealing the mechanisms underlying this confusion, the present project aims to alleviate it in psychotic patients by the use of brain stimulation. The project will thus significantly improve our understanding of these cognitive processes and will also have clinical implications."
Max ERC Funding
1 280 680 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
