Somatic mutations in vascular-wall function and age-associated disease

Introduction

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.

Mutation Impact

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.

Research Gap

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).

Project Objectives

We will create an atlas of somatic mutations in the human arterial wall at single-cell resolution in health and disease. The specific objectives include:

1. Apply single-cell sequencing in arterial tissue to map somatic mutations.
2. Validate the functional significance of somatic mutagenesis in the vascular wall using data on gene regulatory networks relevant to human CVD.
3. Use disease models with induced somatic mutations in VSMC to study the effects.

Methodology

The model will have a mosaic pattern of mutation, and the fate of mutated cells will be mapped by lineage tracing in the development and progression of CVD.

Conclusion

Our research provides insight into the prevalence, nature, and functional significance of somatic genetic events in the healthy and diseased vascular wall.