Thursday, December 26, 2024
12/26/2024
Project Summary/Abstract: Atherosclerosis is a disease of the mid- and large-sized arteries that promotes plaque formation. Plaque development can lead to restricted blood flow, vessel rigidity, and in some cases thrombosis. Atherosclerosis is a major underlying condition that promotes the morbidity and mortality associated with cardiovascular disease, such as heart disease and stroke. Atherosclerosis is mediated by chronic exposure to elevated serum cholesterol which leads to deposition and accumulation of inflammatory cells in the intima-region of the vessel wall. Monocyte infiltration is a hallmark of disease progression where cells differentiate into lipid-laden macrophages, termed “foamy cells”. We interrogated single cell RNA-seq (scRNA-seq) gene expression data from atherosclerotic plaques which identified genes uniquely associated with foamy macrophages, including the myeloid lipid sensor Trem2. Additionally, an unbiased genome-wide Crispr-screen of in vitro derived foamy macrophages found Trem2 was required for oxidized LDL uptake. However, paradoxically, Trem2 was also required for efflux of cholesterol in foamy macrophages. Since Trem2 has been associated with enhanced lipid uptake in adipose macrophages and efflux in microglia, we sought to test its role in atherosclerosis. Using Trem2- knockout and conditional Trem2-deletion approaches, we found Trem2 mediates lipid accumulation in plaque macrophages and loss of Trem2 resulted in a dramatic reduction in atherosclerotic plaque size. Thus, based on our preliminary data, we hypothesize that Trem2 regulates foamy macrophage lipid uptake and survival in atherosclerosis. We have extensive experience studying myeloid cells in atherosclerosis and include newly developed monocyte fate-mapping model to track monocyte differentiation in plaque, and a viral atherosclerosis regression model, which places our lab in unique position to address the questions outlined in this application. In addition, we incorporate a Trem2 agonistic antibody as an approach to complement deletion experiments to determine the mechanisms of Trem2 in atherosclerotic disease. Together, we will address the role of Trem2 in atherosclerosis progression, examine in depth signaling mechanisms in foamy cells that are regulated by Trem2, and determine whether Trem2 is a therapeutic target for intervention. Findings from this study represent potentially highly impactful knowledge for translation of a novel candidate to drive plaque regression in atherosclerosis patients.
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