The European Research Council has awarded two UEF researchers with ERC Starting Grants. The highly competitive grants were awarded to Associate Professor, Academy Research Fellow Minna Kaikkonen-Määttä and Academy Research Fellow Alina Solomon for research projects bringing new insights into the development of atherosclerosis and multimodal, personalized dementia prevention. Only 13 per cent of applicants were funded with the grant aimed at promising researchers with pioneering research projects. The grantees are awarded up to € 1.5 million for a period of five years.
Noncoding genome regions can contribute to atherosclerosis
The ERC Starting Grant enables Minna Kaikkonen-Määttä’s research group at A.I. Virtanen Institute to study the role of noncoding enhancer regions and single nucleotide polymorphisms lying in these regions in the development of coronary artery disease.
Coronary artery disease is the leading cause of death in the Western world. In atherosclerosis, the primary cause of heart disease, accumulation of lipids in the endothelial wall leads to inflammation, plaque formation and ischemia. The cells types of the vessel wall including endothelial cells, smooth muscle cells and macrophages as well as changes in adipose tissue and liver metabolism play a central role in the disease progression. However, little is yet known about the role of specific cell types and their contribution. In order to improve the prevention, diagnosis and treatment of coronary artery disease, a deeper understanding is needed of how genetic and environmental factors contribute to the pathogenesis.
In recent years, genome-wide association studies (GWAS) have discovered hundreds of single nucleotide polymorphisms (SNPs) which are significantly associated with coronary artery disease. However, the SNPs identified by GWAS explain typically only small portion of the trait heritability, and the 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. Therefore, a major priority for understanding disease mechanisms is to understand at the molecular level the function of each CAD loci.
The aim of the ERC funded study is to bring the functional characterization of SNPs associated with CAD risk to date by focusing the 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, the researchers hope to identify causal enhancer variants and their 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 deep phenotypic genomics data from patients has the potential to improve risk characterization, biomarker identification and treatment selection in clinical practice. Ultimately, the research strives for fundamental discoveries and breakthroughs that advance our knowledge of CAD and provides pioneering steps towards taking the growing array of GWAS for translatable results.
The ERC project involves ongoing collaborations with professors Markku Laakso and Jussi Pihlajamäki from University of Eastern Finland, Professor Päivi Pajukanta from University of Los Angeles, Assistant professor Casey Romanoski from University of Arizona and Assistant professor Mete Civelek from University of Virginia.
Towards multimodal, personalized dementia prevention
Alina Solomon from the Institute of Clinical Medicine was awarded the ERC Starting Grant for the Brain Health Toolbox Project with the aim of developing multimodal personalized tools for dementia risk prediction and prevention.
Preventing dementia and Alzheimer disease is a global priority. A new multimodal preventive approach may be most effective in these complex multifactorial conditions. The Brain Health Toolbox is designed to create a seamless continuum from accurate dementia prediction to effective prevention by developing the missing disease models and prediction tools for multimodal prevention and testing them in actual multimodal prevention trials. In addition, the aim is to bridge the gap between non-pharmacological and pharmacological approaches by designing a combined multimodal prevention trial based on a new European adaptive trial platform.
The disease models and prediction tools will be multi-dimensional, based on a broad range of risk factors and biomarker types, including novel markers. An innovative machine learning method will be used for pattern identification and risk profiling to highlight most important contributors to an individual’s overall risk level. This is crucial for early identification of individuals with high dementia risk and/or high likelihood of specific brain pathologies, quantifying an individual’s prevention potential, and longitudinal risk and disease monitoring. Three main Toolbox test scenarios are considered: use for selecting target populations, assessing heterogeneity of intervention effects, and use as trial outcome. The project is based on a unique set-up aligning several new multimodal lifestyle trials aiming to adapt and test non-pharmacological interventions to different geographic, economic and cultural settings, and two reference libraries (observational - large datasets; and interventional - four recently completed pioneering multimodal lifestyle prevention trials). The Brain Health Toolbox covers the entire continuum from general populations to patients with preclinical or prodromal disease stages, and will provide tools for personalized decision-making for dementia prevention.
For further information, please contact:
Associate Professor, Academy Research Fellow Minna Kaikkonen-Määttä, minna.kaikkonen (a) uef.fi, tel. +358 40 355 2413
Academy Research Fellow Alina Solomon, alina.solomon (a) uef.fi, tel. +358 29 4454747
All ERC projects at UEF: https://www.uef.fi/en/web/guest/research/erc-projects