PROJECT SUMMARY/ABSTRACT
Coronary artery disease (CAD) remains a leading cause of death despite the availability of lifesaving pharma-
cological and mechanical interventions. Complementary treatments are desperately needed, particularly for
individuals with advanced disease. Here, we propose foundational work toward realizing a hypothetical `medi-
cal revascularization' that could one day help patients with CAD by extending coronary arterial networks or in-
ducing natural bypasses through collateral arteries. An obstacle to `medical revascularization' is the lack of
known targetable pathways that can stimulate coronary artery growth and collateralization. Our principal ra-
tionale for overcoming this knowledge gap—based on our prior research individually and as a team—is that
studying coronary artery formation during embryonic and fetal development should identify pathways for re-
forming coronary arteries during disease. Since coronary development generates variations in anatomy, we
propose to identify regenerative pathways by studying the human population genetics of coronary artery ana-
tomical variation, or patterning, and then investigating the utility of identified genetic regulators using pre-clini-
cal experimentation. Our long-term goal is to use this information to develop new translational pathways. We
will first accurately classify three coronary patterning phenotypes routinely documented during coronary angi-
ography in the Veteran Affairs Health Care System, including anomalous coronary arteries, coronary domi-
nance, and coronary collateralization, and assess their impact on clinical cardiovascular outcomes nationwide
(Aim 1). Next, we will cross reference this dataset with the Million Veteran Program to identify the genetic de-
terminants through genome wide association studies (GWAS) in >90,000 participants of diverse ancestry, in-
cluding >16,000 African and >6,000 Hispanic American Veterans. Genetic discovery will be extended into the
multi-ancestry Penn Medicine Biobank through replication and meta-analysis. Downstream analyses on GWAS
summary statistics will identify the most compelling candidate causal genes at each susceptibility locus (Aim
2). The function of prioritized candidate genes will be comprehensively tested using mouse genetic manipula-
tions in developmental and injury models and a novel human iPSC-to-artery differentiation method (Aim 3).
The project is innovative because it leverages a combination of the nation's largest integrated health care sys-
tem, the oldest electronic health record system—including one of the most comprehensive registries of coro-
nary catheterization procedures—and the world's largest active biobank to conduct translational research. Ad-
ditionally, candidate genes will be experimentally validated in developmental and pre-clinical assays for coro-
nary artery and collateral formation. This research is significant because it will set the stage for the develop-
ment of novel therapies able to promote the growth of arteries that could substantially improve both the quality
and quantity of life in individuals suffering from CAD.
