Investigating the Pathological Features of Clonal Hematopoiesis-derived Macrophages

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PROJECT SUMMARY Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated condition defined by the expansion of hematopoietic cells that harbor mutations commonly found in leukemia, in the absence of hematological malignancies or related pathologies. CHIP is highly prevalent in the aging community, with about 10-30% of individuals over the age of 70 acquiring the condition, and is associated with an increased mortality rate among the elderly. Surprisingly, this increased mortality rate is largely driven by an elevated risk of atherosclerotic cardiovascular disease (ASCVD). CHIP carriers have been found to have a 2-fold increased risk of myocardial infarction, stroke, and heart failure. Murine studies have shown a causal association of CHIP with ASCVD, largely by upregulating proinflammatory pathways in pathogenic macrophages. Though the use of mouse models has allowed us to gain insight into important mechanisms involving CHIP, there are aspects of human physiology that are not captured in a murine system. This study will utilize a tractable, human primary model of functional CHIP macrophages, along with humanized mouse models to study the pathological features of CHIP-related atherosclerosis. The objective of this proposed study is to determine what mechanisms in human cells are important in CHIP- related ASCVD. The overall hypothesis of this study is that CHIP-related mutations will increase key inflammatory signaling pathways in human myeloid cells that may not necessarily be conserved in mice, contributing to exacerbation of cardiovascular disease. The aims addressed in this proposal are: 1) to determine the transcriptional changes in primary human macrophages under proinflammatory activation, 2) to determine the mechanisms mediating the protective effect of an IL6R variant for CHIP associated CVD in primary human macrophages, and 3) to determine phenotypic changes of macrophages in a chronic inflammation model of clonal hematopoiesis in a humanized murine in vivo system. The use of a primary human macrophage model of CHIP will bridge the gap in knowledge between what has been observed clinically versus what has been observed in murine models of CHIP. Work for this proposal may suggest suitable targets for pharmaceutical intervention.