Project acronym EnDeCAD
Project Enhancers Decoding the Mechanisms Underlying CAD Risk
Researcher (PI) Minna Unelma KAIKKONEN-MÄÄTTÄ
Host Institution (HI) ITA-SUOMEN YLIOPISTO
Call Details Starting Grant (StG), LS4, ERC-2018-STG
Summary In recent years, genome-wide association studies (GWAS) have discovered hundreds of single nucleotide polymorphisms (SNPs) which are significantly associated with coronary artery disease (CAD). However, the SNPs identified by GWAS explain typically only small portion of the trait heritability and vast majority of variants do not have known biological roles. This is explained by variants lying within noncoding regions such as in cell type specific enhancers and additionally ‘the lead SNP’ identified in GWAS may not be the ‘the causal SNP’ but only linked with a trait associated SNP. Therefore, a major priority for understanding disease mechanisms is to understand at the molecular level the function of each CAD loci. In this study we aim to bring the functional characterization of SNPs associated with CAD risk to date by focusing our search for causal SNPs to enhancers of disease relevant cell types, namely endothelial cells, macrophages and smooth muscle cells of the vessel wall, hepatocytes and adipocytes. By combination of massively parallel enhancer activity measurements, collection of novel eQTL data throughout cell types under disease relevant stimuli, identification of the target genes in physical interaction with the candidate enhancers and establishment of correlative relationships between enhancer activity and gene expression we hope to identify causal enhancer variants and link them with target genes to obtain a more complete picture of the gene regulatory events driving disease progression and the genetic basis of CAD. Linking these findings with our deep phenotypic data for cardiovascular risk factors, gene expression and metabolomics has the potential to improve risk prediction, biomarker identification and treatment selection in clinical practice. Ultimately, this research strives for fundamental discoveries and breakthrough that advance our knowledge of CAD and provides pioneering steps towards taking the growing array of GWAS for translatable results.
Summary
In recent years, genome-wide association studies (GWAS) have discovered hundreds of single nucleotide polymorphisms (SNPs) which are significantly associated with coronary artery disease (CAD). However, the SNPs identified by GWAS explain typically only small portion of the trait heritability and vast majority of variants do not have known biological roles. This is explained by variants lying within noncoding regions such as in cell type specific enhancers and additionally ‘the lead SNP’ identified in GWAS may not be the ‘the causal SNP’ but only linked with a trait associated SNP. Therefore, a major priority for understanding disease mechanisms is to understand at the molecular level the function of each CAD loci. In this study we aim to bring the functional characterization of SNPs associated with CAD risk to date by focusing our search for causal SNPs to enhancers of disease relevant cell types, namely endothelial cells, macrophages and smooth muscle cells of the vessel wall, hepatocytes and adipocytes. By combination of massively parallel enhancer activity measurements, collection of novel eQTL data throughout cell types under disease relevant stimuli, identification of the target genes in physical interaction with the candidate enhancers and establishment of correlative relationships between enhancer activity and gene expression we hope to identify causal enhancer variants and link them with target genes to obtain a more complete picture of the gene regulatory events driving disease progression and the genetic basis of CAD. Linking these findings with our deep phenotypic data for cardiovascular risk factors, gene expression and metabolomics has the potential to improve risk prediction, biomarker identification and treatment selection in clinical practice. Ultimately, this research strives for fundamental discoveries and breakthrough that advance our knowledge of CAD and provides pioneering steps towards taking the growing array of GWAS for translatable results.
Max ERC Funding
1 498 647 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym STIMUNO
Project Searching for novel strategies improving cancer immunotherapy
Researcher (PI) Magdalena WINIARSKA
Host Institution (HI) WARSZAWSKI UNIWERSYTET MEDYCZNY
Call Details Starting Grant (StG), LS4, ERC-2018-STG
Summary The main goal of this project is to explore new fundamental pathways involved in the regulation of antitumor immune response. Since the immunosuppressive tumor microenvironment constitutes a key barrier to effective immunotherapy, our predominant ambition is to characterize novel, hitherto unknown metabolic changes that can support the survival of tumor cells and the escape from the immune surveillance.
We have recently discovered a new metabolite within tumor microenvironment with a robust ability to inhibit the activity of immune cells and their potential to kill target tumor cells. Within the project, we plan to corroborate on our preliminary findings in order to establish the role of this factor in mitigating antitumor immune response. To this end, we will determine the level of its production within tumors in murine models. Moreover, we will relate these findings to human data by analysing the immune milieu and the expression of enzymes involved in generation of this metabolic agent in a cohort of cancer patients. We will also investigate the mechanisms by which this factor could perturb the functions of tumor-infiltrating effector cells.
Finally, we aspire to use the knowledge gained during the implementation of this project to propose innovative therapeutic solutions. Specifically, we will investigate whether and how the inhibition of selected enzymes involved in the generation of this new metabolic checkpoint can impact on the efficacy of immunotherapeutic agents, including immune checkpoint inhibitors, arginase inhibitors as well as adoptive therapy with CAR-T cells and CAR-NK cells. We strongly believe that by achieving the goals of our project we will make a significant step forward in order to develop and to design cutting-edge therapeutic strategies. These compelling solutions would further improve the efficacy of tumor immunotherapy, thus contributing to a breakthrough advance in cancer treatment.
Summary
The main goal of this project is to explore new fundamental pathways involved in the regulation of antitumor immune response. Since the immunosuppressive tumor microenvironment constitutes a key barrier to effective immunotherapy, our predominant ambition is to characterize novel, hitherto unknown metabolic changes that can support the survival of tumor cells and the escape from the immune surveillance.
We have recently discovered a new metabolite within tumor microenvironment with a robust ability to inhibit the activity of immune cells and their potential to kill target tumor cells. Within the project, we plan to corroborate on our preliminary findings in order to establish the role of this factor in mitigating antitumor immune response. To this end, we will determine the level of its production within tumors in murine models. Moreover, we will relate these findings to human data by analysing the immune milieu and the expression of enzymes involved in generation of this metabolic agent in a cohort of cancer patients. We will also investigate the mechanisms by which this factor could perturb the functions of tumor-infiltrating effector cells.
Finally, we aspire to use the knowledge gained during the implementation of this project to propose innovative therapeutic solutions. Specifically, we will investigate whether and how the inhibition of selected enzymes involved in the generation of this new metabolic checkpoint can impact on the efficacy of immunotherapeutic agents, including immune checkpoint inhibitors, arginase inhibitors as well as adoptive therapy with CAR-T cells and CAR-NK cells. We strongly believe that by achieving the goals of our project we will make a significant step forward in order to develop and to design cutting-edge therapeutic strategies. These compelling solutions would further improve the efficacy of tumor immunotherapy, thus contributing to a breakthrough advance in cancer treatment.
Max ERC Funding
1 498 750 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
