Project acronym ABC
Project Targeting Multidrug Resistant Cancer
Researcher (PI) Gergely Szakacs
Host Institution (HI) TERMESZETTUDOMANYI KUTATOKOZPONT
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.
Summary
Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.
Max ERC Funding
1 499 640 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym BREATHE
Project BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Researcher (PI) Jordi Sunyer Deu
Host Institution (HI) FUNDACION PRIVADA INSTITUTO DE SALUD GLOBAL BARCELONA
Call Details Advanced Grant (AdG), LS7, ERC-2010-AdG_20100317
Summary Traffic-related air pollution is an important environmental problem that may affect neurodevelopment. Ultrafine particles (UFP) translocate to the brains of experimental animals resulting in local proinflammatory overexpression. As the basic elements for thinking are acquired by developing brains during infancy and childhood, susceptibility may be elevated in early life.
We postulate that traffic-related air pollution (particularly UFPs and metals/hydrocarbons content) impairs neurodevelopment in part via effects on frontal lobe maturation, likely increasing attention-deficit/hyperactivity disorder (ADHD). BREATHE objectives are to develop valid methods to measure children's personal UFP exposure and to develop valid neuroimaging methods to assess correlations between neurobehavior, neurostructural alterations and particle deposition in order to reveal how traffic pollution affects children¿s exposure to key contaminants and brain development, and identify susceptible subgroups.
We have conducted general population birth cohort studies providing preliminary evidence of residential air pollution effects on prenatal growth and mental development.
We aim to demonstrate short and long-term effects on neurodevelopment using innovative epidemiological methods interfaced with environmental chemistry and neuroimaging following 4000 children from 40 schools with contrasting high/low traffic exposure in six linked components involving: repeated psychometric tests, UFP exposure assessment using personal, school and home measurements, gene-environment interactions on inflammation, detoxification pathways and ADHD genome-wide-associated genes, neuroimaging (magnetic resonance imaging/spectroscopy) in ADHD/non-ADHD children, integrative causal modeling using mathematics, and replication in 2900 children with neurodevelopment followed from pregnancy.
We believe the expected results will have worldwide global planning and policy implications.
Summary
Traffic-related air pollution is an important environmental problem that may affect neurodevelopment. Ultrafine particles (UFP) translocate to the brains of experimental animals resulting in local proinflammatory overexpression. As the basic elements for thinking are acquired by developing brains during infancy and childhood, susceptibility may be elevated in early life.
We postulate that traffic-related air pollution (particularly UFPs and metals/hydrocarbons content) impairs neurodevelopment in part via effects on frontal lobe maturation, likely increasing attention-deficit/hyperactivity disorder (ADHD). BREATHE objectives are to develop valid methods to measure children's personal UFP exposure and to develop valid neuroimaging methods to assess correlations between neurobehavior, neurostructural alterations and particle deposition in order to reveal how traffic pollution affects children¿s exposure to key contaminants and brain development, and identify susceptible subgroups.
We have conducted general population birth cohort studies providing preliminary evidence of residential air pollution effects on prenatal growth and mental development.
We aim to demonstrate short and long-term effects on neurodevelopment using innovative epidemiological methods interfaced with environmental chemistry and neuroimaging following 4000 children from 40 schools with contrasting high/low traffic exposure in six linked components involving: repeated psychometric tests, UFP exposure assessment using personal, school and home measurements, gene-environment interactions on inflammation, detoxification pathways and ADHD genome-wide-associated genes, neuroimaging (magnetic resonance imaging/spectroscopy) in ADHD/non-ADHD children, integrative causal modeling using mathematics, and replication in 2900 children with neurodevelopment followed from pregnancy.
We believe the expected results will have worldwide global planning and policy implications.
Max ERC Funding
2 499 230 €
Duration
Start date: 2011-08-01, End date: 2016-07-31
Project acronym CBCD
Project Understanding the basis of cerebellar and brainstem congenital defects: from clinical and molecular characterisation to the development of a novel neuroembryonic in vitro model
Researcher (PI) Enza Maria Valente
Host Institution (HI) FONDAZIONE SANTA LUCIA
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Cerebellar and brainstem congenital defects (CBCDs) are heterogeneous disorders with high pre-and post-natal mortality and morbidity. Their genetic basis and pathogenetic mechanisms are largely unknown, hampering patients’ diagnosis and management and family counselling. This project aims at improve current understanding of primary CBCDs through a multidisciplinary approach combining innovative clinical, neuroimaging, molecular and functional studies, that will be articulated in four workpackages:
WP1- Clinical and neuroimaging studies: collection of detailed data and biological samples from a large cohort of patients covering a broad spectrum of CBCDs, neuroimaging classification based on magnetic resonance imaging and tractography, genotype-phenotype correlates and follow-up studies.
WP2 - Molecular studies on mendelian CBCDs: high-throughput resequencing of ciliary genes to identify pathogenic mutations and genetic modifiers in patients with ciliopathies, identification of novel disease genes, mutation analysis of genes causative of other mendelian CBCDs.
WP3 - Molecular studies on sporadic CBCDs: identification of cryptic chromosomal rearrangements by high resolution SNP-array analysis, selection and mutation analysis of candidate genes mapping to the rearranged regions.
WP4 - Functional studies: optimisation of a novel neuroembryonic in vitro model derived from mouse embryonic stem cells, to test the role of known and candidate disease genes (from WP2 and 3) on cerebellar and brainstem development, define the pathways in which they are involved and the effect of disease-causative mutations.
This project is expected to improve the current CBCD nosology, identify novel genes and mechanisms involved in cerebellar and brainstem development that are responsible for mendelian or sporadic defects, expand the available tools for pre- and post-natal diagnosis and identify clinical-genetic correlates and prognostic indexes.
Summary
Cerebellar and brainstem congenital defects (CBCDs) are heterogeneous disorders with high pre-and post-natal mortality and morbidity. Their genetic basis and pathogenetic mechanisms are largely unknown, hampering patients’ diagnosis and management and family counselling. This project aims at improve current understanding of primary CBCDs through a multidisciplinary approach combining innovative clinical, neuroimaging, molecular and functional studies, that will be articulated in four workpackages:
WP1- Clinical and neuroimaging studies: collection of detailed data and biological samples from a large cohort of patients covering a broad spectrum of CBCDs, neuroimaging classification based on magnetic resonance imaging and tractography, genotype-phenotype correlates and follow-up studies.
WP2 - Molecular studies on mendelian CBCDs: high-throughput resequencing of ciliary genes to identify pathogenic mutations and genetic modifiers in patients with ciliopathies, identification of novel disease genes, mutation analysis of genes causative of other mendelian CBCDs.
WP3 - Molecular studies on sporadic CBCDs: identification of cryptic chromosomal rearrangements by high resolution SNP-array analysis, selection and mutation analysis of candidate genes mapping to the rearranged regions.
WP4 - Functional studies: optimisation of a novel neuroembryonic in vitro model derived from mouse embryonic stem cells, to test the role of known and candidate disease genes (from WP2 and 3) on cerebellar and brainstem development, define the pathways in which they are involved and the effect of disease-causative mutations.
This project is expected to improve the current CBCD nosology, identify novel genes and mechanisms involved in cerebellar and brainstem development that are responsible for mendelian or sporadic defects, expand the available tools for pre- and post-natal diagnosis and identify clinical-genetic correlates and prognostic indexes.
Max ERC Funding
1 367 960 €
Duration
Start date: 2011-08-01, End date: 2018-03-31
Project acronym CGT HEMOPHILIA A
Project Cell and gene therapy based strategies to correct the bleeding phenotype in Hemophilia A
Researcher (PI) Antonia Follenzi
Host Institution (HI) UNIVERSITA DEGLI STUDI DEL PIEMONTE ORIENTALE AMEDEO AVOGADRO
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Currently, haemophilia A cannot be cured. To prevent major bleeding episodes in haemophilia, human Factor VIII (FVIII) protein must be frequently administered as prophylaxis or on demand. This treatment is complicated by its high cost and development of antibodies that neutralize FVIII activity in 20 to 30% of the patients. Therefore, permanent solutions in the form of cell and gene therapy are very attractive for haemophilia A. Recently, we demonstrated in a murine model that liver sinusoidal endothelial cells (LSEC) produce and secrete FVIII, although not exclusively. We have also found that these mice can be treated by reconstitution with wild-type bone marrow, indicating that bone marrow-derived cells, of hematopoietic, mesenchymal or even endothelial origin, can produce and secrete FVIII. Based on these findings in mice, I propose that human LSEC, umbilical cord blood cells, and bone marrow cells might be suitable sources of FVIII to be used for cell replacement therapy for haemophilia A. To advance opportunities for cell and gene therapies in haemophilia A and for identifying additional cell sources of FVIII, I intend to explore whether replacement of liver endothelium and bone marrow in immnocompromised Haemophilia A mice with healthy human cells will provide therapeutic correction. Recently, the possibility of reprogramming mature somatic cells to generate induced pluripotent stem (iPS) cells has enabled the derivation of disease-specific pluripotent cells, thus providing unprecedented experimental platforms to treat human diseases. Therefore, I intend to study whether the generation of patient-specific iPS cells may be applied to cell and gene therapy of coagulation disorders and in particular for the treatment of Haemophilia A. Studies with these novel target cells may impact significantly the future course of Haemophilia A by providing proof-of feasibility of a novel therapy strategies.
Summary
Currently, haemophilia A cannot be cured. To prevent major bleeding episodes in haemophilia, human Factor VIII (FVIII) protein must be frequently administered as prophylaxis or on demand. This treatment is complicated by its high cost and development of antibodies that neutralize FVIII activity in 20 to 30% of the patients. Therefore, permanent solutions in the form of cell and gene therapy are very attractive for haemophilia A. Recently, we demonstrated in a murine model that liver sinusoidal endothelial cells (LSEC) produce and secrete FVIII, although not exclusively. We have also found that these mice can be treated by reconstitution with wild-type bone marrow, indicating that bone marrow-derived cells, of hematopoietic, mesenchymal or even endothelial origin, can produce and secrete FVIII. Based on these findings in mice, I propose that human LSEC, umbilical cord blood cells, and bone marrow cells might be suitable sources of FVIII to be used for cell replacement therapy for haemophilia A. To advance opportunities for cell and gene therapies in haemophilia A and for identifying additional cell sources of FVIII, I intend to explore whether replacement of liver endothelium and bone marrow in immnocompromised Haemophilia A mice with healthy human cells will provide therapeutic correction. Recently, the possibility of reprogramming mature somatic cells to generate induced pluripotent stem (iPS) cells has enabled the derivation of disease-specific pluripotent cells, thus providing unprecedented experimental platforms to treat human diseases. Therefore, I intend to study whether the generation of patient-specific iPS cells may be applied to cell and gene therapy of coagulation disorders and in particular for the treatment of Haemophilia A. Studies with these novel target cells may impact significantly the future course of Haemophilia A by providing proof-of feasibility of a novel therapy strategies.
Max ERC Funding
1 123 000 €
Duration
Start date: 2011-05-01, End date: 2017-04-30
Project acronym CODIR
Project Colonic Disease Investigation by Robotic Hydro-colonoscopy
Researcher (PI) Alfred Cuschieri
Host Institution (HI) UNIVERSITY OF DUNDEE
Call Details Advanced Grant (AdG), LS7, ERC-2010-AdG_20100317
Summary CODIR proposes a new configuration of fundamental and applied biomedical and engineering multidisciplinary research to explore and characterise colon behavior necessary for the project and wider objectives. Scope and focus is on novel robotic hydro-colonoscopy (RHC), which stems from two considerations: (i) replacement of the flexible colonosocope with a patient-friendly system for inspection of the mucosal surface colon and (ii) the very recent concept of hydro-colonoscopy whereby water is used instead of traditional air insufflation. RHC can enable a breakthrough in patient-compliant complete endoscopic examination and biopsy of the colon for the further study of life threatening disorders of the colon commonly categorized as inflmmatory bowel disease, all of unknown aetilogy despite intensive research. CODIR will provide new insights for biomedical investigation and research applicable to many biomedical fields: biologic [absorption of water and electrolyte from the colon, characterisation of surface topograpgy of the colon, mechanical properties of colonic wall], imaging, mechatronics robot functionality and a novel colonic irrigation and filling system. The ambition is to develop a one-stop holistic system which cleans the colon of faecal debris and then introduces a tethered swimming/ submerging robot for inspection of the mucosal aspect of colon under the control of a clinician operating the endoluminal mini-robot from a control console. A secondary, very important outcome of CODIR is to increase patient compliance (currently 50%) for screening colonoscopy in early diagnosis of colorectal cancer, the worlds second commonest cancer. RHC can overcome major disadvantages of existing colonoscopy examination: discomfort, sedation, thus increasing compliance and enabling future research.
Summary
CODIR proposes a new configuration of fundamental and applied biomedical and engineering multidisciplinary research to explore and characterise colon behavior necessary for the project and wider objectives. Scope and focus is on novel robotic hydro-colonoscopy (RHC), which stems from two considerations: (i) replacement of the flexible colonosocope with a patient-friendly system for inspection of the mucosal surface colon and (ii) the very recent concept of hydro-colonoscopy whereby water is used instead of traditional air insufflation. RHC can enable a breakthrough in patient-compliant complete endoscopic examination and biopsy of the colon for the further study of life threatening disorders of the colon commonly categorized as inflmmatory bowel disease, all of unknown aetilogy despite intensive research. CODIR will provide new insights for biomedical investigation and research applicable to many biomedical fields: biologic [absorption of water and electrolyte from the colon, characterisation of surface topograpgy of the colon, mechanical properties of colonic wall], imaging, mechatronics robot functionality and a novel colonic irrigation and filling system. The ambition is to develop a one-stop holistic system which cleans the colon of faecal debris and then introduces a tethered swimming/ submerging robot for inspection of the mucosal aspect of colon under the control of a clinician operating the endoluminal mini-robot from a control console. A secondary, very important outcome of CODIR is to increase patient compliance (currently 50%) for screening colonoscopy in early diagnosis of colorectal cancer, the worlds second commonest cancer. RHC can overcome major disadvantages of existing colonoscopy examination: discomfort, sedation, thus increasing compliance and enabling future research.
Max ERC Funding
2 999 948 €
Duration
Start date: 2011-08-01, End date: 2016-07-31
Project acronym DIAG-CANCER
Project Diagnosis, Screening and Monitoring of Cancer Diseases via Exhaled Breath Using an Array of Nanosensors
Researcher (PI) Hossam Haick
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Cancer is rapidly becoming the greatest health hazard of our days. The most widespread cancers, are lung cancer (LC), breast cancer (BC), colorectal cancer (CC), and prostate cancer (PC). The impact of the various techniques used for diagnosis, screening and monitoring
these cancers is either uncertain and/or inconvenient for the patients. This proposal aims to create a low-cost, easy-to-use and noninvasive screening method for LC, BC, CC, and PC based on breath testing with a novel nanosensors approach. With this in mind, we propose to:
(a) modify an array of nanosensors based on Au nanoparticles for obtaining highly-sensitive detection levels of breath biomarkers of cancer; and
(b) investigate the use of the developed array in a clinical study.
Towards this end, we will collect suitable breath samples from patients and healthy controls in a clinical trial and test the feasibility of the device to detect LC, BC, CC, and PC, also in the presence of other diseases.
We will then investigate possible ways to identify the stage of the disease, monitor the response to cancer
treatment, and to identify cancer subtypes. Further, we propose that the device can be used for monitoring of cancer patients during and after treatment. The chemical nature of the cancer biomarkers will be identified through spectrometry techniques.
The proposed approach would be used outside specialist settings and could considerably lessen the burden on the health budgets, both through the low cost of the proposed all-inclusive cancer test, and through earlier and, hence, more cost-effective cancer treatment.
Summary
Cancer is rapidly becoming the greatest health hazard of our days. The most widespread cancers, are lung cancer (LC), breast cancer (BC), colorectal cancer (CC), and prostate cancer (PC). The impact of the various techniques used for diagnosis, screening and monitoring
these cancers is either uncertain and/or inconvenient for the patients. This proposal aims to create a low-cost, easy-to-use and noninvasive screening method for LC, BC, CC, and PC based on breath testing with a novel nanosensors approach. With this in mind, we propose to:
(a) modify an array of nanosensors based on Au nanoparticles for obtaining highly-sensitive detection levels of breath biomarkers of cancer; and
(b) investigate the use of the developed array in a clinical study.
Towards this end, we will collect suitable breath samples from patients and healthy controls in a clinical trial and test the feasibility of the device to detect LC, BC, CC, and PC, also in the presence of other diseases.
We will then investigate possible ways to identify the stage of the disease, monitor the response to cancer
treatment, and to identify cancer subtypes. Further, we propose that the device can be used for monitoring of cancer patients during and after treatment. The chemical nature of the cancer biomarkers will be identified through spectrometry techniques.
The proposed approach would be used outside specialist settings and could considerably lessen the burden on the health budgets, both through the low cost of the proposed all-inclusive cancer test, and through earlier and, hence, more cost-effective cancer treatment.
Max ERC Funding
1 200 000 €
Duration
Start date: 2011-01-01, End date: 2014-12-31
Project acronym DNA-AMP
Project DNA Adduct Molecular Probes: Elucidating the Diet-Cancer Connection at Chemical Resolution
Researcher (PI) Shana Jocette Sturla
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Bulky DNA adducts formed from chemical carcinogens dictate structure, reactivity, and mechanism of chemical-biological reactions; therefore, their identification is central to evaluating and mitigating cancer risk. Natural food components, or others associated with certain food preparations or metabolic conversions, initiate potentially damaging genetic mutations after forming DNA adducts, which contribute critically to carcinogenesis, despite the fact that they are typically repaired biochemically and they are formed at extremely low levels. This situation places significant limitations on our ability to understand the role of formation, repair, and mutagenesis on the basis of the complex DNA reactivity profiles of food components. The long-term goals of this research are to contribute basic knowledge and advanced experimental tools required to understand, on the basis of chemical structure, the contributions of chronic, potentially adverse, dietary chemical carcinogen exposure to cancer development. It is proposed that a new class of synthetic nucleosides, devised on the basis of preliminary discoveries made in the independent laboratory of the applicant, will serve as molecular probes for bulky DNA adducts and can be effectively used to study and AMPlify, i.e. as a sensitive diagnostic tool, low levels of chemically-specific modes of DNA damage. The proposed research is a chemical biology-based approach to the study of carcinogenesis. Experiments involve chemical synthesis, thermodynamic and kinetic characterization DNA-DNA and enzyme-DNA interactions, and nanoparticle-based molecular probes. The proposal describes a potentially ground-breaking approach for profiling the biological reactivities of chemical carcinogens, and we expect to gain fundamental knowledge and chemical tools that can contribute to the prevention of diseases influenced by gene-environment interactions.
Summary
Bulky DNA adducts formed from chemical carcinogens dictate structure, reactivity, and mechanism of chemical-biological reactions; therefore, their identification is central to evaluating and mitigating cancer risk. Natural food components, or others associated with certain food preparations or metabolic conversions, initiate potentially damaging genetic mutations after forming DNA adducts, which contribute critically to carcinogenesis, despite the fact that they are typically repaired biochemically and they are formed at extremely low levels. This situation places significant limitations on our ability to understand the role of formation, repair, and mutagenesis on the basis of the complex DNA reactivity profiles of food components. The long-term goals of this research are to contribute basic knowledge and advanced experimental tools required to understand, on the basis of chemical structure, the contributions of chronic, potentially adverse, dietary chemical carcinogen exposure to cancer development. It is proposed that a new class of synthetic nucleosides, devised on the basis of preliminary discoveries made in the independent laboratory of the applicant, will serve as molecular probes for bulky DNA adducts and can be effectively used to study and AMPlify, i.e. as a sensitive diagnostic tool, low levels of chemically-specific modes of DNA damage. The proposed research is a chemical biology-based approach to the study of carcinogenesis. Experiments involve chemical synthesis, thermodynamic and kinetic characterization DNA-DNA and enzyme-DNA interactions, and nanoparticle-based molecular probes. The proposal describes a potentially ground-breaking approach for profiling the biological reactivities of chemical carcinogens, and we expect to gain fundamental knowledge and chemical tools that can contribute to the prevention of diseases influenced by gene-environment interactions.
Max ERC Funding
1 500 000 €
Duration
Start date: 2010-09-01, End date: 2015-08-31
Project acronym DYNAMIT
Project Deep Tissue Optoacoustic Imaging for Tracking of Dynamic Molecular and Functional Events
Researcher (PI) Daniel Razansky
Host Institution (HI) HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary The ability to visualize biological processes in living organisms continuously, instead of at discrete time points, holds a great promise for studies of functional and molecular events, disease progression and treatment monitoring. Optical spectrum is particularly attractive for biological interrogations as it can impart highly versatile contrast of cellular and sub-cellular function as well as employ highly specific contrast agents and markers not available for other modalities. However, technical limitations arising from intense light scattering in living tissues bound the main-stream of high resolution optical imaging applications to microscopic studies at shallow depths that do not allow the exploration of the full potential of novel classes of agents for volumetric imaging of entire organs, small animals or human tissues.
To overcome limitations of the current imaging techniques, this proposal aims to develop a novel high performance optoacoustic imaging technology and explore its groundbreaking potential for neuroimaging and monitoring of cardiovascular disease. I will undertake a substantial technological step that will bring optoacoustic imaging to a real time (video rate) high resolution performance level the like of which has not existed so far. The resulting technique will be able to image several millimeters to centimeters into living small animals and potentially humans, with both high spatial resolution and sensitivity, being independent of photon scattering. This will make it suitable for attaining high dynamic contrast in intact tissues and an ideal candidate for both intrinsic and targeted biomarker-based imaging. It is hypothesized that these unparalleled imaging capabilities will allow observations of new classes of dynamic interactions at different time scales, from relatively slow varying inflammation-related molecular events to video rate visualization of neuronal activity in deep brain regions, otherwise invisible with other imaging methods.
Summary
The ability to visualize biological processes in living organisms continuously, instead of at discrete time points, holds a great promise for studies of functional and molecular events, disease progression and treatment monitoring. Optical spectrum is particularly attractive for biological interrogations as it can impart highly versatile contrast of cellular and sub-cellular function as well as employ highly specific contrast agents and markers not available for other modalities. However, technical limitations arising from intense light scattering in living tissues bound the main-stream of high resolution optical imaging applications to microscopic studies at shallow depths that do not allow the exploration of the full potential of novel classes of agents for volumetric imaging of entire organs, small animals or human tissues.
To overcome limitations of the current imaging techniques, this proposal aims to develop a novel high performance optoacoustic imaging technology and explore its groundbreaking potential for neuroimaging and monitoring of cardiovascular disease. I will undertake a substantial technological step that will bring optoacoustic imaging to a real time (video rate) high resolution performance level the like of which has not existed so far. The resulting technique will be able to image several millimeters to centimeters into living small animals and potentially humans, with both high spatial resolution and sensitivity, being independent of photon scattering. This will make it suitable for attaining high dynamic contrast in intact tissues and an ideal candidate for both intrinsic and targeted biomarker-based imaging. It is hypothesized that these unparalleled imaging capabilities will allow observations of new classes of dynamic interactions at different time scales, from relatively slow varying inflammation-related molecular events to video rate visualization of neuronal activity in deep brain regions, otherwise invisible with other imaging methods.
Max ERC Funding
1 452 650 €
Duration
Start date: 2010-10-01, End date: 2015-09-30
Project acronym ECONENDLIFE
Project The economic evaluation of end of life care
Researcher (PI) Joanna Coast
Host Institution (HI) THE UNIVERSITY OF BIRMINGHAM
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Making choices about the health care that we provide in society is a fundamental and unavoidable issue. Economic evaluation aids this decision-making by supplying information about costs and benefits of different interventions. For end of life care, however, current evaluative frameworks are inadequate because they focus only on health and only on the patient. Amartya Sen’s capability approach offers an alternative and appropriate framework for evaluating end of life care and this programme aims to build on my ground-breaking work in the application of Sen’s approach to measurement within economic evaluation. Six key tasks will be undertaken: (i) defining the ‘end of life’ period using semi-structured interviews with key stakeholders; (ii) assessing the construct validity and sensitivity to change of a descriptive system for evaluating capabilities related to end of life care; (iii) eliciting values for this descriptive system from the general public and patients at the end of life using the best-worst scaling technique; (iv) developing a descriptive system to evaluate the impact on families’ capabilities of end of life care, using in-depth interviews to develop conceptual attributes; (v) conducting exploratory theoretical and methodological work on weighting across measures; and (vi) exploring views of the public and key stakeholders about appropriate decision-rules for end of life care, using a combination of focus groups and in-depth interviews. The work involves frontier research at the interface between health, economics and human development. It will address the significant methodological issues associated with the economic evaluation of end of life care and so advance the state-of-the-art to a point where robust economic evaluation of end of life care is feasible.
Summary
Making choices about the health care that we provide in society is a fundamental and unavoidable issue. Economic evaluation aids this decision-making by supplying information about costs and benefits of different interventions. For end of life care, however, current evaluative frameworks are inadequate because they focus only on health and only on the patient. Amartya Sen’s capability approach offers an alternative and appropriate framework for evaluating end of life care and this programme aims to build on my ground-breaking work in the application of Sen’s approach to measurement within economic evaluation. Six key tasks will be undertaken: (i) defining the ‘end of life’ period using semi-structured interviews with key stakeholders; (ii) assessing the construct validity and sensitivity to change of a descriptive system for evaluating capabilities related to end of life care; (iii) eliciting values for this descriptive system from the general public and patients at the end of life using the best-worst scaling technique; (iv) developing a descriptive system to evaluate the impact on families’ capabilities of end of life care, using in-depth interviews to develop conceptual attributes; (v) conducting exploratory theoretical and methodological work on weighting across measures; and (vi) exploring views of the public and key stakeholders about appropriate decision-rules for end of life care, using a combination of focus groups and in-depth interviews. The work involves frontier research at the interface between health, economics and human development. It will address the significant methodological issues associated with the economic evaluation of end of life care and so advance the state-of-the-art to a point where robust economic evaluation of end of life care is feasible.
Max ERC Funding
999 177 €
Duration
Start date: 2011-04-01, End date: 2015-09-30
Project acronym EPICHEART
Project Interplay of genetic, nutrient and lifestyle factors on incidence of coronary disease: EPIC-Heart
Researcher (PI) John Navid Danesh
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE
Call Details Advanced Grant (AdG), LS7, ERC-2010-AdG_20100317
Summary A major new frontier in biomedicine is to identify interactions of specific components of nature and nurture in determining risk of complex diseases. Coronary heart disease (CHD) - the single leading cause of death in Europe - is jointly determined by genetic and lifestyle factors. It is unknown, however, how diet, nutrients, and lifestyle factors modulate genetic susceptibility. For scientific and public health reasons, there is a strategic need to study such interactions reliably. There is a unique opportunity for a cost-effective and powerful study because we have:
-conducted detailed assessment of diet and other lifestyle factors in 520K participants in a pan-European prospective study
-identified >12K incident CHD cases accrued during >5M person-years at risk
-identified a random sub-cohort of >15K participants without CHD to serve as referents
-commenced assay of lipid and other markers in 12K cases and 15K referents
-prepared DNA for genetic assay.
In 12K CHD cases and 15K referents, we will assay: >217K genetic variants contained in the state-of-the-art metabochip; 37 fatty acids; and vitamin D metabolites. Analyses will focus on: discovery of interactions; causal evaluation of biomarkers; CHD risk scores.
The findings should open new horizons and contribute towards: 1) explaining missing heritability 2) shaping nutritional guidelines 3) personalising preventive medicine 4) defining approaches to modify genetic susceptibility by avoiding deleterious lifestyles 5) identifying biomarkers that are priority therapeutic targets and 6) innovative prognostic tools.
Gene-lifestyle interplay is a major future growth area. This world-leading study will enhance Europes strengths in public health, nutrition and genetic epidemiology, and create a valuable future resource.
Summary
A major new frontier in biomedicine is to identify interactions of specific components of nature and nurture in determining risk of complex diseases. Coronary heart disease (CHD) - the single leading cause of death in Europe - is jointly determined by genetic and lifestyle factors. It is unknown, however, how diet, nutrients, and lifestyle factors modulate genetic susceptibility. For scientific and public health reasons, there is a strategic need to study such interactions reliably. There is a unique opportunity for a cost-effective and powerful study because we have:
-conducted detailed assessment of diet and other lifestyle factors in 520K participants in a pan-European prospective study
-identified >12K incident CHD cases accrued during >5M person-years at risk
-identified a random sub-cohort of >15K participants without CHD to serve as referents
-commenced assay of lipid and other markers in 12K cases and 15K referents
-prepared DNA for genetic assay.
In 12K CHD cases and 15K referents, we will assay: >217K genetic variants contained in the state-of-the-art metabochip; 37 fatty acids; and vitamin D metabolites. Analyses will focus on: discovery of interactions; causal evaluation of biomarkers; CHD risk scores.
The findings should open new horizons and contribute towards: 1) explaining missing heritability 2) shaping nutritional guidelines 3) personalising preventive medicine 4) defining approaches to modify genetic susceptibility by avoiding deleterious lifestyles 5) identifying biomarkers that are priority therapeutic targets and 6) innovative prognostic tools.
Gene-lifestyle interplay is a major future growth area. This world-leading study will enhance Europes strengths in public health, nutrition and genetic epidemiology, and create a valuable future resource.
Max ERC Funding
2 499 154 €
Duration
Start date: 2011-05-01, End date: 2017-04-30
