PROJECT 1: Modulating blood cell heterogeneity to reduce cardiovascular inflammation

ABSTRACT This proposal focuses on how the atherogenic state leads to the selective outgrowth of cell clones that are epigenetically restricted in their behaviors. It is based on prior work demonstrating that stem and progenitor hematopoietic cells are not highly plastic responding in different ways to different challenges. Rather, they have functional attributes scripted in their epigenome and subsets of clones selectively respond to challenges. Cells are selected by heritable functions; they are not blank slates in which a functional phenotype is induced. In the context of cardiovascular disease (CVD), this means that the atherogenic state selects for specific clones that then propagate atherogenesis in a self-reinforcing manner. We hypothesize that this occurs not just among hematopoietic cells but also in the bone marrow stromal cell subsets we have defined and that stroma and blood co-conspire to accelerate CVD. In this proposal, we test clonal outgrowth in both types of cells under different types of atherogenic states and in the context of specific neural modifiers of atherogenesis. We then test whether modifying epigenetic features of cells can modulate CVD. Our goal is to define means of interrupting the pathogenic systems biology of CVD.