Macrophages in Cardiovascular Health

Massachusetts General Hospital, Boston MA

Investigators

Abstract

Inflammation is seen as an unrealized therapeutic opportunity in cardiovascular disease (CVD), and the field is poised to recapitulate immunomodulatory drug breakthroughs that recently happened for cancer patients. In this application, I propose expanding our understanding of innate immunity in CVD, a necessary step to identify therapeutic targets that do not sacrifice host defense. I will ask the overarching question how macrophages influence cardiovascular health and disease. I will focus on these innate immune cells because they are among the most numerous in the healthy and diseased arterial wall and the myocardium, and because these cells are not only influential for their surrounding tissue environment but also undergo vast quantitative and phenotypical changes when exposed to cardiovascular risk factors. For example, bone marrow-derived macrophages can destabilize the arterial wall, triggering ischemic events. Physical activity protects against these events, an insight that may hold lessons for drug development. Now is an opportune time to unleash single cell imaging and omics to identify harmful macrophage subsets and their functions, pursuing regulatory pathways that can serve as immunomodulatory targets. In addition to their actions in destination tissues, the application focusses on mechanisms that lead to overproduction of monocytes in the bone marrow of patients with increased cardiovascular risk, because monocytosis associates with patients' cardiovascular mortality. My mission is strengthened by a strong translational perspective: the discovery pipeline is guided by clinical data and observations. I will tackle three major goals: 1. to understand the role of macrophages in preserving cardiovascular health, 2. to illuminate their contributions to CVD and 3. to use this insight to define new therapeutic targets for female and male CVD patients. My ultimate goal for this program is a macrophage drug target for CVD, meeting the high level of ambition stipulated by the program's RFA.