Cellular and Molecular Mechanisms of Atherosclerosis

Atherosclerotic cardiovascular disease (CVD) remains the leading cause of death worldwide and substantial residual CVD risk persists despite effective LDL-cholesterol (LDL-C) lowering. In this context, we propose an investigation of mechanisms of plaque stabilization and destabilization focused on novel functions of macrophages (Mϕ) and vascular stromal cells, and their crosstalk, in mouse models and human CVD. Our overarching hypothesis, pursued through three highly integrated Projects and two Scientific Cores is that inflammation and the efferocytosis-resolution cycle in macrophages regulate plaque stability through crosstalk with other macrophages and stromal cells and that detailed examination of the cell and molecular mechanisms may provide opportunities for novel CVD treatments, including in patients with clonal hematopoiesis, an emerging CVD risk factor. To address this hypothesis, Aim 1 will assess novel genes and pathways regulating macrophage efferocytosis in atherosclerosis and mechanistically based therapeutic approaches to improve efferocytosis and stabilize plaques. Aim 2 will investigate the impact of inflammatory cross-talk from Mϕs to stromal cells on plaque fibrous cap formation. Aim 3 will pursue translational relevance by examining the relationship of clonal hematopoiesis mutations and efferocytosis genes to features of plaque stability using human carotid plaque samples from the Munich Vascular Biobank. We will pursue these overall aims in three highly integrated Projects, and two Scientific Cores coordinated by our Administrative Core. Our program will use mouse models of disease and human atherosclerotic plaques to assess multiple genetic and therapeutic interventions designed to stabilize plaques and reduce CVD risk. The projects will extensively leverage the Scientific Cores to apply harmonized bioinformatic methods to single cell -omics data (Core B: Bioinformatics and Biostatistics) and atherosclerosis phenotyping of mouse and human lesions(Core C: Mouse and Human Atherosclerosis Tissue Core). Cross-cutting biological and technical innovations include mice that accurately model clonal hematopoiesis, cell lineage tracing mouse models, advanced bioinformatics for sc and spatial data, and new spatial transcriptomics approaches in human carotid plaques. Collaboration permeates the entire PPG as a result of three years of preparatory work and preliminary studies. Each project addresses complementary questions that together provide opportunities to understand new clinically relevant paradigms of atherosclerosis stability and instability with the expectation to provide opportunities for novel mechanism-based targeted therapeutic intervention to reduce CVD beyond LDL-C lowering. Thus, our proposed PPG is mechanistically, clinically and translationally significant and relevant to public health.