Project acronym CIRCUITASSEMBLY
Project Development of functional organization of the visual circuits in mice
Researcher (PI) Keisuke Yonehara
Host Institution (HI) AARHUS UNIVERSITET
Call Details Starting Grant (StG), LS5, ERC-2014-STG
Summary The key organizing principles that characterize neuronal systems include asymmetric, parallel, and topographic connectivity of the neural circuits. The main aim of my research is to elucidate the key principles underlying functional development of neural circuits by focusing on those organizing principles. I choose mouse visual system as my model since it contains all of these principles and provides sophisticated genetic tools to label and manipulate individual circuit components. My research is based on the central hypothesis that the mechanisms of brain development cannot be fully understood without first identifying individual functional cell types in adults, and then understanding how the functions of these cell types become established, using cell-type-specific molecular and synaptic mechanisms in developing animals. Recently, I have identified several transgenic mouse lines in which specific cell types in a visual center, the superior colliculus, are labeled with Cre recombinase in both developing and adult animals. Here I will take advantage of these mouse lines to ask fundamental questions about the functional development of neural circuits. First, how are distinct sensory features processed by the parallel topographic neuronal pathways, and how do they contribute to behavior? Second, what are the molecular and synaptic mechanisms that underlie developmental circuit plasticity for forming parallel topographic neuronal maps in the brain? Third, what are the molecular mechanisms that set up spatially asymmetric circuit connectivity without the need for sensory experience? I predict that my insights into the developmental mechanism of asymmetric, parallel, and topographic connectivity and circuit plasticity will be instructive when studying other brain circuits which contain similar organizing principles.
Summary
The key organizing principles that characterize neuronal systems include asymmetric, parallel, and topographic connectivity of the neural circuits. The main aim of my research is to elucidate the key principles underlying functional development of neural circuits by focusing on those organizing principles. I choose mouse visual system as my model since it contains all of these principles and provides sophisticated genetic tools to label and manipulate individual circuit components. My research is based on the central hypothesis that the mechanisms of brain development cannot be fully understood without first identifying individual functional cell types in adults, and then understanding how the functions of these cell types become established, using cell-type-specific molecular and synaptic mechanisms in developing animals. Recently, I have identified several transgenic mouse lines in which specific cell types in a visual center, the superior colliculus, are labeled with Cre recombinase in both developing and adult animals. Here I will take advantage of these mouse lines to ask fundamental questions about the functional development of neural circuits. First, how are distinct sensory features processed by the parallel topographic neuronal pathways, and how do they contribute to behavior? Second, what are the molecular and synaptic mechanisms that underlie developmental circuit plasticity for forming parallel topographic neuronal maps in the brain? Third, what are the molecular mechanisms that set up spatially asymmetric circuit connectivity without the need for sensory experience? I predict that my insights into the developmental mechanism of asymmetric, parallel, and topographic connectivity and circuit plasticity will be instructive when studying other brain circuits which contain similar organizing principles.
Max ERC Funding
1 500 000 €
Duration
Start date: 2015-04-01, End date: 2020-03-31
Project acronym DE-ORPHAN
Project DEtermination of Orphan Receptor PHysiological Agonists and sigNals
Researcher (PI) David Erik Immanuel Gloriam
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Starting Grant (StG), LS7, ERC-2014-STG
Summary G protein-coupled receptors make up both the largest membrane protein and drug target families. DE-ORPHAN aims to determine the close functional context; specifically physiological agonists and signaling pathways; and provide the first research tool compounds, of orphan peptide receptors.
Determination of physiological agonists (aka de-orphanization), by high-throughput screening has largely failed. We will introduce a new research strategy: 1) developing highly innovative bioinformatics methods for handpicking of all orphan receptor targets and candidate ligand screening libraries; and 2) employing a screening technique that can measure all signaling pathways simultaneously.
The first potent and selective pharmacological tool compounds will be identified by chemoinformatic design of focused screening libraries. We will establish the ligands’ structure-activity relationships important for biological activity and further optimization towards drugs.
The first potent and selective Gs- and G12/13 protein inhibitors will be designed by structure-based re-optimization from a recent crystal structure of a Gq-inhibitor complex, and applied to determine orphan receptor signaling pathways and ligand pathway-bias. They will open up for efficient dissection of important signaling networks and development of drugs with fewer side effects.
DE-ORPHANs design hypotheses are based on unique computational methods to analyze protein and ligand similarities and are founded on genomic and protein sequences, structural data and ligands. The interdisciplinary research strategy applies multiple ligands acting independently but in concert to provide complementary receptor characterization. The results will allow the research field to advance into studies of receptor functions and exploitation of druggable targets, ligands and mechanisms. Which physiological insights and therapeutic breakthroughs will we witness when these receptors find their place in human pharmacology and medicine?
Summary
G protein-coupled receptors make up both the largest membrane protein and drug target families. DE-ORPHAN aims to determine the close functional context; specifically physiological agonists and signaling pathways; and provide the first research tool compounds, of orphan peptide receptors.
Determination of physiological agonists (aka de-orphanization), by high-throughput screening has largely failed. We will introduce a new research strategy: 1) developing highly innovative bioinformatics methods for handpicking of all orphan receptor targets and candidate ligand screening libraries; and 2) employing a screening technique that can measure all signaling pathways simultaneously.
The first potent and selective pharmacological tool compounds will be identified by chemoinformatic design of focused screening libraries. We will establish the ligands’ structure-activity relationships important for biological activity and further optimization towards drugs.
The first potent and selective Gs- and G12/13 protein inhibitors will be designed by structure-based re-optimization from a recent crystal structure of a Gq-inhibitor complex, and applied to determine orphan receptor signaling pathways and ligand pathway-bias. They will open up for efficient dissection of important signaling networks and development of drugs with fewer side effects.
DE-ORPHANs design hypotheses are based on unique computational methods to analyze protein and ligand similarities and are founded on genomic and protein sequences, structural data and ligands. The interdisciplinary research strategy applies multiple ligands acting independently but in concert to provide complementary receptor characterization. The results will allow the research field to advance into studies of receptor functions and exploitation of druggable targets, ligands and mechanisms. Which physiological insights and therapeutic breakthroughs will we witness when these receptors find their place in human pharmacology and medicine?
Max ERC Funding
1 499 926 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym DUB-DECODE
Project Systematic Decoding of Deubiquitylase-Regulated Signaling Networks
Researcher (PI) Chuna Ram Choudhary
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Consolidator Grant (CoG), LS2, ERC-2014-CoG
Summary Cellular processes are largely governed by sophisticated protein posttranslational modification (PTM)-dependent signaling networks, and a systematic understanding of regulatory PTM-based networks is a key goal in modern biology. Ubiquitin is a small, evolutionarily conserved signaling protein that acts as a PTM after being covalently conjugated to other proteins. Reversible ubiquitylation forms the most versatile and largest eukaryote-exclusive signaling system, and regulates the stability and function of almost all proteins in cells. Deubiquitylases (DUBs) are ubiquitin-specific proteases that remove substrate-conjugated ubiquitin, and thereby regulate virtually all ubiquitylation-dependent signaling. Because of their central role in ubiquitin signaling, DUBs have essential functions in mammalian physiology and development, and the dysregulated expression and mutation of DUBs is frequently associated with human diseases. Despite their vital functions, very little is known about the proteins and ubiquitylation sites that are regulated by DUBs and this knowledge gap is hampering our understanding of the molecular mechanisms by which DUBs control diverse biological processes. Recently, we developed a mass spectrometry-based proteomics approach that allowed unbiased and site-specific quantification of ubiquitylation on a systems-wide scale. Here we propose to comprehensively investigate DUB-regulated ubiquitin signaling in human cells. We will integrate interdisciplinary approaches to develop next-generation cell models and innovative proteomic technologies to systematically decode DUB function in human cells. This will enable a novel and detailed understanding of DUB-regulated signaling networks, and open up new avenues for further research into the mechanisms and biological functions of ubiquitylation and of ubiquitin-like modifiers.
Summary
Cellular processes are largely governed by sophisticated protein posttranslational modification (PTM)-dependent signaling networks, and a systematic understanding of regulatory PTM-based networks is a key goal in modern biology. Ubiquitin is a small, evolutionarily conserved signaling protein that acts as a PTM after being covalently conjugated to other proteins. Reversible ubiquitylation forms the most versatile and largest eukaryote-exclusive signaling system, and regulates the stability and function of almost all proteins in cells. Deubiquitylases (DUBs) are ubiquitin-specific proteases that remove substrate-conjugated ubiquitin, and thereby regulate virtually all ubiquitylation-dependent signaling. Because of their central role in ubiquitin signaling, DUBs have essential functions in mammalian physiology and development, and the dysregulated expression and mutation of DUBs is frequently associated with human diseases. Despite their vital functions, very little is known about the proteins and ubiquitylation sites that are regulated by DUBs and this knowledge gap is hampering our understanding of the molecular mechanisms by which DUBs control diverse biological processes. Recently, we developed a mass spectrometry-based proteomics approach that allowed unbiased and site-specific quantification of ubiquitylation on a systems-wide scale. Here we propose to comprehensively investigate DUB-regulated ubiquitin signaling in human cells. We will integrate interdisciplinary approaches to develop next-generation cell models and innovative proteomic technologies to systematically decode DUB function in human cells. This will enable a novel and detailed understanding of DUB-regulated signaling networks, and open up new avenues for further research into the mechanisms and biological functions of ubiquitylation and of ubiquitin-like modifiers.
Max ERC Funding
1 972 570 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym LimitMDR
Project Utilizing evolutionary interactions to limit multidrug resistance
Researcher (PI) Morten Otto Alexander Sommer
Host Institution (HI) DANMARKS TEKNISKE UNIVERSITET
Call Details Starting Grant (StG), LS2, ERC-2014-STG
Summary Drug resistance is limiting our ability to treat most infectious diseases and forms of cancer. Indeed this relentless evolution is the major driver of treatment failure for diseases that are responsible for over half of the global disease related mortality. Yet, the underlying principles that guide this evolutionary response are poorly understood, in particular with regards to understanding the impact of multidrug treatment.
LimitMDR will characterize evolutionary trajectories leading to multidrug resistance in response to individual and combination drug treatment through the execution of large-scale adaptive evolution experiment with two bacterial pathogens followed by genome sequencing and phenotyping. This effort will enable testing of contrasting hypotheses regarding the evolution of multidrug resistance in response to combination treatment.
We will characterize the cause-and-effect of resistance and sensitivity mutations identified in our global data set and map comprehensive fitness landscapes of mutations accumulated during drug resistance evolution to understand the evolutionary dynamics underlying resistance evolution. To accomplish these bold goals we shall develop novel multiplexed methodologies enabling unprecedented scale of construction and phenotypic testing of identified mutations. While genetic epistasis is considered of key importance to resistance evolution most studies focus on mutations within an individual gene. Through the development of a novel experimental approach we shall elucidate complex epistatic interaction networks between mutations accumulated during resistance evolution.
Finally, we will conduct mechanistic studies to uncover the mechanisms of collateral sensitivity. These studies will shed light on this underappreciated phenomenon, which is of critical relevance to drug discovery and the evolution of drug resistance. In conclusion LimitMDR will develop groundbreaking novel methodologies and scientific insights that will c
Summary
Drug resistance is limiting our ability to treat most infectious diseases and forms of cancer. Indeed this relentless evolution is the major driver of treatment failure for diseases that are responsible for over half of the global disease related mortality. Yet, the underlying principles that guide this evolutionary response are poorly understood, in particular with regards to understanding the impact of multidrug treatment.
LimitMDR will characterize evolutionary trajectories leading to multidrug resistance in response to individual and combination drug treatment through the execution of large-scale adaptive evolution experiment with two bacterial pathogens followed by genome sequencing and phenotyping. This effort will enable testing of contrasting hypotheses regarding the evolution of multidrug resistance in response to combination treatment.
We will characterize the cause-and-effect of resistance and sensitivity mutations identified in our global data set and map comprehensive fitness landscapes of mutations accumulated during drug resistance evolution to understand the evolutionary dynamics underlying resistance evolution. To accomplish these bold goals we shall develop novel multiplexed methodologies enabling unprecedented scale of construction and phenotypic testing of identified mutations. While genetic epistasis is considered of key importance to resistance evolution most studies focus on mutations within an individual gene. Through the development of a novel experimental approach we shall elucidate complex epistatic interaction networks between mutations accumulated during resistance evolution.
Finally, we will conduct mechanistic studies to uncover the mechanisms of collateral sensitivity. These studies will shed light on this underappreciated phenomenon, which is of critical relevance to drug discovery and the evolution of drug resistance. In conclusion LimitMDR will develop groundbreaking novel methodologies and scientific insights that will c
Max ERC Funding
1 492 453 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym Local State
Project State Formation Through the Local Production of Property and Citizenship
Researcher (PI) Christian Lund
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Advanced Grant (AdG), SH2, ERC-2014-ADG
Summary The key concern of the proposed research is how political power is established and reproduced through the production of the fundamental social contracts of property and citizenship. We will re-define the research on so-called failed and weak states, by examining what political authority is actually exercised rather than measuring how they fall short of theoretical ideals.
In developing countries with legal and institutional pluralism, no single institution exercises the political authority as such. Different institutions compete to define and enforce rights to property and citizenship. This is most visible at the local level, yet it has implications for theorizing the state as such. Hence, investigating the social production of property and citizenship is a way to study state formation. We study local institutions that exercise political authority and govern access to resources, and recognition of these rights. What institution guarantees what claims as rights, and, especially, how, is crucial, as it leads to the recognition of that particular institution as a political authority. We therefore study statutory as well as non-statutory institutions. We are not simply looking for property deeds and passports etc. issued by statutory government as measurements of political authority. Rather, we look for secondary forms of recognition ‘issued’ by non-statutory institutions that represent mutual acknowledgements of claims even without a narrow legal endorsement. Dynamics such as these are fundamental for a concise understanding of developing country state formation processes.
Ten country studies with rural and urban field sites will be conducted. We focus on concrete controversies. We collect data at several levels and from different sources, including resident groups, land users, local civil servants, local politicians and business-owners, as well as large-scale contractors, municipal politicians and administrators.
Summary
The key concern of the proposed research is how political power is established and reproduced through the production of the fundamental social contracts of property and citizenship. We will re-define the research on so-called failed and weak states, by examining what political authority is actually exercised rather than measuring how they fall short of theoretical ideals.
In developing countries with legal and institutional pluralism, no single institution exercises the political authority as such. Different institutions compete to define and enforce rights to property and citizenship. This is most visible at the local level, yet it has implications for theorizing the state as such. Hence, investigating the social production of property and citizenship is a way to study state formation. We study local institutions that exercise political authority and govern access to resources, and recognition of these rights. What institution guarantees what claims as rights, and, especially, how, is crucial, as it leads to the recognition of that particular institution as a political authority. We therefore study statutory as well as non-statutory institutions. We are not simply looking for property deeds and passports etc. issued by statutory government as measurements of political authority. Rather, we look for secondary forms of recognition ‘issued’ by non-statutory institutions that represent mutual acknowledgements of claims even without a narrow legal endorsement. Dynamics such as these are fundamental for a concise understanding of developing country state formation processes.
Ten country studies with rural and urban field sites will be conducted. We focus on concrete controversies. We collect data at several levels and from different sources, including resident groups, land users, local civil servants, local politicians and business-owners, as well as large-scale contractors, municipal politicians and administrators.
Max ERC Funding
2 469 285 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym METALS
Project Formation and Characterization of Protein Post-Translational Modifications and Assessment of Cellular Responses by Application of Metals in Biological Systems
Researcher (PI) Frank Kjeldsen
Host Institution (HI) SYDDANSK UNIVERSITET
Call Details Consolidator Grant (CoG), LS9, ERC-2014-CoG
Summary The chemistry of metals is rich and viewed in a biological context its diversity is crucial for a multitude of molecular functions in the living cell. Many of these reactions are very attractive to both academia and industry. In this proposal, I plan to develop novel applications of metal compounds to solve immediate challenges in mass spectrometry-based proteome research, but also will assess the potential risks of using nano-sized metals in our society. First, it is important to develop an efficient enzyme-independent method to synthesize large amounts of biologically relevant C-terminal amidated peptides. Presently, C-terminal peptide amidation poses a challenge in pharmaceutical production due to limitations of the two enzymes used for this purpose. The suggested approach in METALS will examine the specific binding of uranyl to artificially phosphorylated recombinant peptides. Data reveal that subsequent UV irradiation produces C-terminal amidated peptides. I will attempt to minimize the bias inherent in current phosphopeptide analysis, which comes from inefficient inhibition of phosphatases during cell lysis. Application of a recently developed gallium complex during cell lysis should limit the extent of this bias by binding phosphorylated proteins. The neutral conditions involved with the gallium complex reaction should also facilitate the possibility of enrichment of acid labile phospho-histidine peptides of which only a handful have been characterized. Finally, humans are now exposed to increasing amounts of artificially nano-metals applied via consumer products, food packages, and cosmetics. I will investigate this problem using advanced mass spectrometry, confocal microscopy, and biochemical assays of the response of human neural cells to nano-metal particles. The particular focus area will be to elucidate whether the action of nanoparticles in human neural cells may shed new light on understanding of diseases like Parkinson´s disease.
Summary
The chemistry of metals is rich and viewed in a biological context its diversity is crucial for a multitude of molecular functions in the living cell. Many of these reactions are very attractive to both academia and industry. In this proposal, I plan to develop novel applications of metal compounds to solve immediate challenges in mass spectrometry-based proteome research, but also will assess the potential risks of using nano-sized metals in our society. First, it is important to develop an efficient enzyme-independent method to synthesize large amounts of biologically relevant C-terminal amidated peptides. Presently, C-terminal peptide amidation poses a challenge in pharmaceutical production due to limitations of the two enzymes used for this purpose. The suggested approach in METALS will examine the specific binding of uranyl to artificially phosphorylated recombinant peptides. Data reveal that subsequent UV irradiation produces C-terminal amidated peptides. I will attempt to minimize the bias inherent in current phosphopeptide analysis, which comes from inefficient inhibition of phosphatases during cell lysis. Application of a recently developed gallium complex during cell lysis should limit the extent of this bias by binding phosphorylated proteins. The neutral conditions involved with the gallium complex reaction should also facilitate the possibility of enrichment of acid labile phospho-histidine peptides of which only a handful have been characterized. Finally, humans are now exposed to increasing amounts of artificially nano-metals applied via consumer products, food packages, and cosmetics. I will investigate this problem using advanced mass spectrometry, confocal microscopy, and biochemical assays of the response of human neural cells to nano-metal particles. The particular focus area will be to elucidate whether the action of nanoparticles in human neural cells may shed new light on understanding of diseases like Parkinson´s disease.
Max ERC Funding
1 798 750 €
Duration
Start date: 2015-09-01, End date: 2021-02-28
Project acronym SCORA
Project A systematic characterization of human regulatory architectures and their determinants of regulatory activity
Researcher (PI) Robin Andersson
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Starting Grant (StG), LS2, ERC-2014-STG
Summary Enhancers control the correct spatio-temporal activation of gene expression. A comprehensive characterization of the properties and regulatory activities of enhancers as well as their target genes is therefore crucial to understand the regulation and dysregulation of differentiation, homeostasis and cell type specificity.
Genome-wide chromatin assays have provided insight into the properties and complex architectures by which enhancers regulate genes, but the understanding of their mechanisms is fragmented and their regulatory targets are mostly unknown. Several factors may confound the inference and interpretation of regulatory enhancer activity. There are likely many kinds of regulatory architectures with distinct levels of output and flexibility. Despite this, most state-of-the-art genome-wide studies only consider a single model. In addition, chromatin-based analysis alone does not provide clear insight into function or activity.
This project aims to systematically characterize enhancer architectures and delineate what determines their: (1) restricted spatio-temporal activity; (2) robustness to regulatory genetic variation; and (3) dynamic activities over time. My work has shown enhancer transcription to be the most accurate classifier of enhancer activity to date. This data permits unprecedented modeling of regulatory architectures via enhancer-promoter co-expression linking. Careful computational analysis of such data from appropriate experimental systems has a great potential for distinguishing the different modes of regulation and their functional impact.
The outcomes have great potential for providing us with new insights into mechanisms of transcriptional regulation. The results will be particularly relevant to interpretation of regulatory genetic variations. Ultimately, knowing the characteristics and conformations of enhancer architectures will increase our ability to link variation in non-coding DNA to phenotypic outcomes like disease susceptibility.
Summary
Enhancers control the correct spatio-temporal activation of gene expression. A comprehensive characterization of the properties and regulatory activities of enhancers as well as their target genes is therefore crucial to understand the regulation and dysregulation of differentiation, homeostasis and cell type specificity.
Genome-wide chromatin assays have provided insight into the properties and complex architectures by which enhancers regulate genes, but the understanding of their mechanisms is fragmented and their regulatory targets are mostly unknown. Several factors may confound the inference and interpretation of regulatory enhancer activity. There are likely many kinds of regulatory architectures with distinct levels of output and flexibility. Despite this, most state-of-the-art genome-wide studies only consider a single model. In addition, chromatin-based analysis alone does not provide clear insight into function or activity.
This project aims to systematically characterize enhancer architectures and delineate what determines their: (1) restricted spatio-temporal activity; (2) robustness to regulatory genetic variation; and (3) dynamic activities over time. My work has shown enhancer transcription to be the most accurate classifier of enhancer activity to date. This data permits unprecedented modeling of regulatory architectures via enhancer-promoter co-expression linking. Careful computational analysis of such data from appropriate experimental systems has a great potential for distinguishing the different modes of regulation and their functional impact.
The outcomes have great potential for providing us with new insights into mechanisms of transcriptional regulation. The results will be particularly relevant to interpretation of regulatory genetic variations. Ultimately, knowing the characteristics and conformations of enhancer architectures will increase our ability to link variation in non-coding DNA to phenotypic outcomes like disease susceptibility.
Max ERC Funding
1 436 293 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym uPET
Project Molecular imaging and targeted therapy of the aggressive phenotype: development of uPAR theranostics for cancer patients
Researcher (PI) Andreas Kjaer
Host Institution (HI) REGION HOVEDSTADEN
Call Details Advanced Grant (AdG), LS7, ERC-2014-ADG
Summary For practice of personalized medicine in cancer, non-invasive tools for diagnosing at the molecular level are needed. Molecular imaging methods are capable of this while at the same time circumventing sampling error as the whole tumor burden is evaluated.
We recently developed and performed the first-ever clinical PET scan of uPAR, a proteolytic system known to be strongly associated with metastatic potential in most cancer forms. We believe this new concept of uPAR-PET is a major breakthrough and has the potential to become one of the most used PET tracers as it fulfils unmet needs in prostate and breast cancer. Based on this, together with additional proof-of-concept data we obtained on targeting uPAR for optical imaging and radionuclide therapy, we now plan to develop and take into patients these new technologies for improved outcome.
Specific aims are to develop and translate into human use:
1. A PET uPAR imaging ligand platform for visualization of the aggressive phenotype and risk-stratification to be used in tailoring therapy, e.g. in prostate cancer to decide whether prostatectomy is necessary.
2. uPAR-PET combined with simultaneous 13C-hyperpolarized pyruvate MRSI (Warburg effect). This will increase prognostic power, refine tumor phenotyping and thereby allow for better tailoring of therapy and early prediction of treatment response.
3. A uPAR optical imaging technology for guiding removal of cancer tissue during surgery. This will help delineate cancer tissue for removal while leaving healthy tissue behind. We expect better outcome with removal of less tissue.
4. Selective radionuclide therapies targeting uPAR positive, invasive cancer cells using β or α emitters. Dose planning will be performed using uPAR-PET imaging. This image-therapy pairing is also known as theranostics.
Our endeavour is ambitious, yet realistic considering our competencies and track-record. We expect cancer patients to benefit from our new methods within the 5 year time-frame.
Summary
For practice of personalized medicine in cancer, non-invasive tools for diagnosing at the molecular level are needed. Molecular imaging methods are capable of this while at the same time circumventing sampling error as the whole tumor burden is evaluated.
We recently developed and performed the first-ever clinical PET scan of uPAR, a proteolytic system known to be strongly associated with metastatic potential in most cancer forms. We believe this new concept of uPAR-PET is a major breakthrough and has the potential to become one of the most used PET tracers as it fulfils unmet needs in prostate and breast cancer. Based on this, together with additional proof-of-concept data we obtained on targeting uPAR for optical imaging and radionuclide therapy, we now plan to develop and take into patients these new technologies for improved outcome.
Specific aims are to develop and translate into human use:
1. A PET uPAR imaging ligand platform for visualization of the aggressive phenotype and risk-stratification to be used in tailoring therapy, e.g. in prostate cancer to decide whether prostatectomy is necessary.
2. uPAR-PET combined with simultaneous 13C-hyperpolarized pyruvate MRSI (Warburg effect). This will increase prognostic power, refine tumor phenotyping and thereby allow for better tailoring of therapy and early prediction of treatment response.
3. A uPAR optical imaging technology for guiding removal of cancer tissue during surgery. This will help delineate cancer tissue for removal while leaving healthy tissue behind. We expect better outcome with removal of less tissue.
4. Selective radionuclide therapies targeting uPAR positive, invasive cancer cells using β or α emitters. Dose planning will be performed using uPAR-PET imaging. This image-therapy pairing is also known as theranostics.
Our endeavour is ambitious, yet realistic considering our competencies and track-record. We expect cancer patients to benefit from our new methods within the 5 year time-frame.
Max ERC Funding
2 072 000 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym VITAL
Project The Vitality of Disease - Quality of Life in the Making
Researcher (PI) Ayo Juhani Wahlberg
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Starting Grant (StG), SH2, ERC-2014-STG
Summary Epidemiological reports from around the world suggest that more people than ever before are living with (especially chronic) diseases. As a consequence, sustained efforts to reduce morbidity and mortality rates have been joined by systematised efforts to improve the lives – the quality of life – of those living with disease in ways that are measurable and auditable.
VITAL will focus on the making of ‘quality of life’. While social studies of medicine have of late been marked by a ‘bio-turn’, it is apparent that within contemporary medicine, life is envisaged as much more than cellular and molecular activity; it is also a social activity and a personal experience. Not only is life sustained, it is also lived. In recent decades, morbid living – living with disease – has come to be the object of novel forms of knowledge, expertise, measurement and management while also generating new medical practices and attendant ways of relating to oneself.
VITAL suggests a shift in attention from the ways in which the social sciences have previously studied morbid living and related issues of quality of life. Rather than continue longstanding efforts to understand how people cope with disease or to refine definitions and instruments for measuring the quality of life of the sick, in VITAL we will empirically study the co-production of ‘quality of life’ within healthcare through four ethnographically-grounded studies of how ‘quality of life’ is assembled, mobilised, negotiated and practiced in concrete medical settings. The four studies will focus on how knowledge about living with disease is assembled and mobilised, on the one hand, and how morbid living is negotiated and practiced on the other.
The key outcomes of VITAL will be theoretical advancement of understandings of vitality in the 21st century beyond molecular biology and methodological innovation to facilitate empirical study of co-production processes that involve social science knowledge and practice.
Summary
Epidemiological reports from around the world suggest that more people than ever before are living with (especially chronic) diseases. As a consequence, sustained efforts to reduce morbidity and mortality rates have been joined by systematised efforts to improve the lives – the quality of life – of those living with disease in ways that are measurable and auditable.
VITAL will focus on the making of ‘quality of life’. While social studies of medicine have of late been marked by a ‘bio-turn’, it is apparent that within contemporary medicine, life is envisaged as much more than cellular and molecular activity; it is also a social activity and a personal experience. Not only is life sustained, it is also lived. In recent decades, morbid living – living with disease – has come to be the object of novel forms of knowledge, expertise, measurement and management while also generating new medical practices and attendant ways of relating to oneself.
VITAL suggests a shift in attention from the ways in which the social sciences have previously studied morbid living and related issues of quality of life. Rather than continue longstanding efforts to understand how people cope with disease or to refine definitions and instruments for measuring the quality of life of the sick, in VITAL we will empirically study the co-production of ‘quality of life’ within healthcare through four ethnographically-grounded studies of how ‘quality of life’ is assembled, mobilised, negotiated and practiced in concrete medical settings. The four studies will focus on how knowledge about living with disease is assembled and mobilised, on the one hand, and how morbid living is negotiated and practiced on the other.
The key outcomes of VITAL will be theoretical advancement of understandings of vitality in the 21st century beyond molecular biology and methodological innovation to facilitate empirical study of co-production processes that involve social science knowledge and practice.
Max ERC Funding
1 499 770 €
Duration
Start date: 2015-06-01, End date: 2020-05-31
