Project acronym CARDIOPREVENT
Project INTEGRATION OF GENOMICS AND CARDIOMETABOLIC PLASMA BIOMARKERS FOR IMPROVED PREDICTION AND PRIMARY PREVENTION OF CARDIOVASCULAR DISEASE
Researcher (PI) Olle Sten Melander
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), LS7, ERC-2011-StG_20101109
Summary "By taking advantage of great experience in genetic and cardiovascular epidemiology and some of the largest cohorts in the world including 60 000 unique individuals, the applicant aims at (1) improving CVD risk prediction and (2) identifying mechanisms causally related to CVD development in order to provide novel targets for drug discovery and targeted life style interventions for use in primary prevention.
In SUBPROJECT 1 we aim at identifying disease causing alleles of loci implicated in CVD by Genome Wide Association Studies (GWAS) and to identify rare alleles with large impact on human CVD. We thus perform whole exome and targeted sequencing in early CVD cases and healthy controls and evaluate all identified variants by relating them to incident CVD in 60.000 individuals. Further, we will create a score of all validated CVD gene variants and test whether such a score improves clinical risk assessment over and above traditional risk factors.
In SUBPROJECT 2 we test whether the plasma metabolome- a phenotype representing the product of dietary intake and inherent (e.g. genetic) metabolism- differs between incident CVD cases and controls and between individuals with high and low CVD genetic risk. We further test whether a life style intervention differentially alters the plasma metabolome between individuals with high and low CVD genetic risk. Finally, we will elucidate the mechanisms underlying CVD genetic associations by testing whether myocardial expression of such genes are affected by experimental myocardial infarction (MI) and whether heart function, MI size and the plasma metabolome are affected by adenoviral myocardial CVD gene transfer in rats.
In SUBPROJECT 3 we test whether glucose metabolism and CVD risk factors can be ameliorated by suppressing vasopressin (VP) by increased water intake in humans. Finally, we test which of the 3 VP receptors is responsible for adverse glucometabolic VP effects in rats by specific VP receptor pharmacological studies."
Summary
"By taking advantage of great experience in genetic and cardiovascular epidemiology and some of the largest cohorts in the world including 60 000 unique individuals, the applicant aims at (1) improving CVD risk prediction and (2) identifying mechanisms causally related to CVD development in order to provide novel targets for drug discovery and targeted life style interventions for use in primary prevention.
In SUBPROJECT 1 we aim at identifying disease causing alleles of loci implicated in CVD by Genome Wide Association Studies (GWAS) and to identify rare alleles with large impact on human CVD. We thus perform whole exome and targeted sequencing in early CVD cases and healthy controls and evaluate all identified variants by relating them to incident CVD in 60.000 individuals. Further, we will create a score of all validated CVD gene variants and test whether such a score improves clinical risk assessment over and above traditional risk factors.
In SUBPROJECT 2 we test whether the plasma metabolome- a phenotype representing the product of dietary intake and inherent (e.g. genetic) metabolism- differs between incident CVD cases and controls and between individuals with high and low CVD genetic risk. We further test whether a life style intervention differentially alters the plasma metabolome between individuals with high and low CVD genetic risk. Finally, we will elucidate the mechanisms underlying CVD genetic associations by testing whether myocardial expression of such genes are affected by experimental myocardial infarction (MI) and whether heart function, MI size and the plasma metabolome are affected by adenoviral myocardial CVD gene transfer in rats.
In SUBPROJECT 3 we test whether glucose metabolism and CVD risk factors can be ameliorated by suppressing vasopressin (VP) by increased water intake in humans. Finally, we test which of the 3 VP receptors is responsible for adverse glucometabolic VP effects in rats by specific VP receptor pharmacological studies."
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-12-01, End date: 2016-11-30
Project acronym PROTEINSEQ
Project Sensitive, specific high-throughput plasma proteome analysis via ProteinSeq
Researcher (PI) Dag Ake Ulf Landegren
Host Institution (HI) UPPSALA UNIVERSITET
Call Details Advanced Grant (AdG), LS7, ERC-2011-ADG_20110310
Summary Despite increasing interest in biomarkers to diagnose and distinguish diseases and select treatment few new protein biomarkers are being successfully validated. Important explanations for the limited success are poor specificity and sensitivity of detection of plasma proteins using current assays, and inability to analyze large numbers of markers and samples. Improved assays should provide access to plasma protein biomarkers at levels below current detection thresholds, potentially reflecting disease processes anywhere in the body at early stages. They should also distinguish closely similar protein variants. The assays should furthermore assess numerous markers in parallel with limited consumption of biobank samples.
The aim of this project is to enable investigations of protein biomarkers at entirely new levels of performance. The basis of the proposal is our expertise in molecular tools and specifically an approach to protein analysis that addresses the above requirements.
This technology is now ready to be scaled for large-volume, high-performance assays with the following characteristics: 1) Unsurpassed specificity via simultaneous detection of three epitopes on any target protein. 2) Amplifiable DNA strands form upon specific detection, permitting ultrasensitive detection. 3) Only appropriate reagent combinations result in amplifiable reporter strands, overcoming obstacles to multiplex protein detection. 4) Tag sequences in the amplified DNA strands identify the detected proteins and the investigated samples, allowing digital information of protein abundance to be retrieved via next generation DNA sequencing of multiplex reactions for large numbers of patients in single runs.
I propose to set up and apply assays of a thousand proteins in parallel in small plasma samples, and in a subproject I will target proteins on a novel and promising class of cancer biomarkers – exosomes.
Summary
Despite increasing interest in biomarkers to diagnose and distinguish diseases and select treatment few new protein biomarkers are being successfully validated. Important explanations for the limited success are poor specificity and sensitivity of detection of plasma proteins using current assays, and inability to analyze large numbers of markers and samples. Improved assays should provide access to plasma protein biomarkers at levels below current detection thresholds, potentially reflecting disease processes anywhere in the body at early stages. They should also distinguish closely similar protein variants. The assays should furthermore assess numerous markers in parallel with limited consumption of biobank samples.
The aim of this project is to enable investigations of protein biomarkers at entirely new levels of performance. The basis of the proposal is our expertise in molecular tools and specifically an approach to protein analysis that addresses the above requirements.
This technology is now ready to be scaled for large-volume, high-performance assays with the following characteristics: 1) Unsurpassed specificity via simultaneous detection of three epitopes on any target protein. 2) Amplifiable DNA strands form upon specific detection, permitting ultrasensitive detection. 3) Only appropriate reagent combinations result in amplifiable reporter strands, overcoming obstacles to multiplex protein detection. 4) Tag sequences in the amplified DNA strands identify the detected proteins and the investigated samples, allowing digital information of protein abundance to be retrieved via next generation DNA sequencing of multiplex reactions for large numbers of patients in single runs.
I propose to set up and apply assays of a thousand proteins in parallel in small plasma samples, and in a subproject I will target proteins on a novel and promising class of cancer biomarkers – exosomes.
Max ERC Funding
2 499 600 €
Duration
Start date: 2012-03-01, End date: 2017-02-28
Project acronym risk factors cancer
Project Genetic and environmental risk factors for common malignant tumours especially breast cancer and melanoma
Researcher (PI) Lars Håkan Olsson
Host Institution (HI) LUNDS UNIVERSITET
Call Details Advanced Grant (AdG), LS7, ERC-2011-ADG_20110310
Summary A prerequisite for prevention or early diagnosis of a tumour disease is that environmental and/or genetic risk factors are characterized in order to better define risk groups. The present research proposal focus on common malignant tumours, especially breast cancer and malignant melanoma . By combining risk factor studies on endogenous and exogenous environmental, and genetic risk factors and its interaction, the aim is to better characterize strong determinants of risk. The project also aims at better understanding the mechanisms of disease and for different exposures, such as sun exposure and different hormonal exposures, obtain a global assessment of possible positive and negative health and disease effects. The infrastructure includes large population based cohort and case-control studies, pathological and clinical patient information, biobanks from cancer patients and controls, availability of excellent genomic resources and an extensive network of national and international collaborations. Very often it has been possible to work out from a population based perspective. Both for breast cancer and melanoma the research group has identified important genes or modifiers of dominant predisposing genes as well as environmental or constitutional risk factors. Through an extensive international collaboration gene and gene-environemnt interaction studies are undertaken. The ulitmate goal for the new knowledge is to prevent or early diagnose the malignancy. In hereditary cancer and for some of the hormonal exposures successful results already are seen. The applicant has been involved more than 30 years in epidemiological research of cancer, and published more than 400 publications in international journals and fostered a large number of PhD students.
Summary
A prerequisite for prevention or early diagnosis of a tumour disease is that environmental and/or genetic risk factors are characterized in order to better define risk groups. The present research proposal focus on common malignant tumours, especially breast cancer and malignant melanoma . By combining risk factor studies on endogenous and exogenous environmental, and genetic risk factors and its interaction, the aim is to better characterize strong determinants of risk. The project also aims at better understanding the mechanisms of disease and for different exposures, such as sun exposure and different hormonal exposures, obtain a global assessment of possible positive and negative health and disease effects. The infrastructure includes large population based cohort and case-control studies, pathological and clinical patient information, biobanks from cancer patients and controls, availability of excellent genomic resources and an extensive network of national and international collaborations. Very often it has been possible to work out from a population based perspective. Both for breast cancer and melanoma the research group has identified important genes or modifiers of dominant predisposing genes as well as environmental or constitutional risk factors. Through an extensive international collaboration gene and gene-environemnt interaction studies are undertaken. The ulitmate goal for the new knowledge is to prevent or early diagnose the malignancy. In hereditary cancer and for some of the hormonal exposures successful results already are seen. The applicant has been involved more than 30 years in epidemiological research of cancer, and published more than 400 publications in international journals and fostered a large number of PhD students.
Max ERC Funding
1 200 000 €
Duration
Start date: 2012-04-01, End date: 2017-03-31
