A Mechanistic and Translational Research Program Linking Impaired Resolution, Defective Efferocytosis, and Clonal Hematopoiesis to the Formation of Clinically Dangerous Atherosclerotic Plaques

Project 1 Narrative The Tabas R35 program will explore new, highly interrelated concepts related to four key areas in which critical gaps in atherosclerotic cardiovascular disease exist: inflammation resolution & efferocytosis (safe clearance of dead cells); pathophysiology of the minority of atherosclerotic lesions that are most clinically important; immunometabolism in macrophages (how macrophages process molecules to alter function); and aging- related clonal hematopoiesis (expansion of blood cells that is common in aging). The flexibility and forward- looking nature of this R35 program will allow expansion of these areas into human atheroma tissue studies, human genetics, and studies with genetically engineered human macrophages to complement the human genetic studies. Successful completion of this R35 program will address key gaps in our knowledge of how the most clinically dangerous atherosclerotic plaques develop; lead to the design of novel therapeutic strategies; and promote the training and mentoring of young scientists in this critical area of research. 1