Project Summary
Each year, millions of patients worldwide receive open vascular reconstructions (such as bypass vein grafting)
to treat occlusive cardiovascular diseases. Unfortunately, post-surgery failure, primarily due to lumen-narrowing
neointimal hyperplasia (IH), occurs at unacceptably high rates leading to tremendous human and financial costs.
IH is formed primarily by the vascular smooth muscle cells (SMCs) that undergo phenotypic transition, with
dysregulated epigenetic remodeling now recognized as a root problem. We have obtained promising data to
show that DOT1L (disruptor of telomeric silencing 1-like), an epigenetic histone code writer, is a potential master
target for IH mitigation. DOT1L is upregulated in human IH tissues. Pharmacologic inhibition and molecular
silencing of DOT1L mitigated SMC phenotypic transition and abated IH in animal models. We generated SMC-
specific DOT1L knockout mice and found that the absence of DOT1L in SMCs inhibited the development of IH.
Toward translation of the basic findings with DOT1L into human applications, we designed a prototype nano-
platform called Epi^NanoPaint for sustained drug delivery that is tailored for open vascular reconstructions.
When used to deliver the DOT1L-selective inhibitor, Pinometostat, Epi^NanoPaint mitigated IH in obese Zucker
rats following vein grafting. These findings support the premise that DOT1L is a master pathogenic target that
dictates SMC phenotypic transition and IH progression. In Aim 1, we will focus on dissecting the physiology of
DOT1L in modulating SMC function associated with IH using our novel mouse models. We will also delineate
the mechanism behind the epigenetic role of DOT1L in controlling IH using a combination of epigenomic,
transcriptomic, and biochemical assays. In Aim 2, we will optimize the Epi^NanoPaint platform to achieve safe
and effective delivery of therapeutic reagents for open vascular surgery application. We will then conduct pre-
clinical studies to establish the risk-benefits of the selected Epi^NanoPaint product to treat IH using animal
models of vein grafting. This project is innovative, as it will advance understanding of DOT1L’s role as an
epigenetic determinant of IH, and also develop a therapeutic prototype conveniently suitable for open vascular
reconstructions.
