Abstract

Despite tremendous progress in cardiovascular research, we still have an incomplete understanding of the precise cell states, transcriptional programs, and regulatory mechanism involved in atherosclerosis and heart failure. I hypothesize: (1) in human coronary artery disease, genetic variation acts in a cell state specific manner to perturb the gene regulatory network and drive smooth muscle cell and fibroblast trans- differentiation into the neo-intima and (2) macrophages signal to fibroblasts via IL-1b through a Runx1 gene regulatory network to drive activation and cardiac fibrosis. To test these hypotheses, we will employ a reverse translation paradigm: starting with human tissue, we will use single cell multi omics to characterize the genomic, transcriptional, and regulatory landscape in coronary artery disease and heart failure. In vivo we will utilize lineage tracing to fate map smooth muscle cells and activated fibroblasts driving disease and use neutralizing antibodies and conditional knockouts to perturb the macrophage- fibroblast axis. Our findings provide a framework for connecting genetic risk to cell state activation in coronary artery disease and putative regulators involved in the inflammatory-fibrosis axis in heart failure.

Committee Chair

Kory Lavine

Committee Members

Nathan Stitziel, Benjamin Humphreys; Douglas Mann; Rafael Kramann; Samantha Morris

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Computational & Systems Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

6-4-2026

Language

English (en)

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