📋 Tender Overview
Somatic Mutations In Vascular-Wall Function And Age-Associated Disease
Genetic Insight Into Cardiovascular Diseaseatherosclerosis Is A Chronic Disease Characterised By The Buildup Of Plaque Within The Arteries, Which Can Lead To Their Narrowing And Hardening, Potentially Causing Various Cardiovascular Problems, Including Heart Attacks And Strokes. The Theory That Atherosclerotic Plaques Originate From Vascular Smooth Muscle Cells (Vsmcs) Is Not New And Recent Evidence Supports The Accumulation Of Somatic Mutations In These Cells During Ageing. Funded By The European Research Council, The Somaticart Project Aims To Analyse Somatic Mutations In The Arterial Wall, Linking Them To Age-Related Cardiovascular Disease. Researchers Will Create A Single-Cell Atlas Of Somatic Mutations In Healthy And Diseased Arterial Walls, Shedding Light On Somatic Genetic Events In Vascular Health And Disease.
Funded Under
European Research Council (Erc)
Total Cost
€ 2 532 795,00
Eu Contribution
€ 2 532 795,00
Coordinated By
Karolinska Institutet
Sweden
Objective
Already in 1973, Benditt and Benditt found that the atherosclerotic plaque was clonal and proposed that it was a neoplasm of vascular smooth muscle cells (VSMC). Recent technical advances have made it possible to analyze somatic mutations in human tissues and show that somatic cells accumulate thousands of mutations during development and aging. While most of the mutations are harmless, some either contribute to disease and aging or are directly disease-causative, as in the formation of tumors in cancer. The arterial wall is in part composed of clonal VSMC elements, making this tissue particularly vulnerable to somatic mutagenesis. However, detailed analysis and insight into the extent of somatic variance in the vascular tissue is lacking. Here we plan to analyze the somatic mutations in the arterial wall and relate it to age-associated cardiovascular disease (CVD). We will create an atlas of somatic mutations in the human arterial wall at single-cell resolution in health and disease. We will apply single-cell sequencing in arterial tissue to map somatic mutations. Functional significance of somatic mutagenesis in the vascular wall will be validated using data on gene regulatory networks of relevance in human CVD and disease models with induced somatic mutations in VSMC. The model will have a mosaic pattern of mutation and fate of mutated cells will be mapped by lineage tracing in the development and progression of CVD. Our research provides insight into the prevalence, nature and functional significance of somatic genetic events in the healthy and diseased vascular wall.
