My laboratory is interested in the vascular biology of atherosclerosis, restenosis, and the vessel wall response to injury. These processes greatly limit the effectiveness and durability of all types of cardiovascular interventions including angioplasty, stenting, and bypass surgery. We are primarily interested in the molecular pathways which govern the growth and phenotypic state of endothelial and smooth muscle cells at sites of blood vessel injury. We have also had a long-standing interest in the local delivery of genes, small molecules and drugs to blood vessels, as both a research tool and as a potential therapeutic approach to modulate vascular healing in patients. Our program is translational in nature, seeking to identify new therapeutic targets and to validate them in both preclinical animal models and human subjects. It is complemented by a clinical research program that examines biomarkers and imaging surrogates of vascular remodeling in patients underoing peripheral bypass or percutaneous revascularizations.
Over the last several years, our basic laboratory studies have focused in two areas. The first is the elucidation of a pathway of cell survival/growth control that represents an opportunity for drug targeting of vascular proliferation. A key element in this pathway is survivin (SVV), a member of the Inhibitor of Apoptosis (IAP) family, and its mitochondrial chaperones from the heat shock protein (Hsp) family. Ongoing studies seek to identify the regulation of SVV and Hsp expression and function in vascular smooth muscle cells, and their subcellular specialized roles. Proteomic and genetic (gene and oligonucleotide-based) approaches are employed to modulate this pathway in-vitro and in-vivo. This work is currently supported by the National Heart, Lung, and Blood Institute (HL085157). A second area of basic investigation has been the elucidation of pathways of resolution of inflammation in vascular cells. Novel endogenous compounds (resolvins, protectins, lipoxins) derived from fatty acid precursors have been identified that specifically turn off inflammation in the context of infection, and there is increasing evidence for their importance in cardiovascular and other diseases. We have been at the forefront of identifying the role of these compounds in vascular injury resolution. This work is currently supported by institutional funds and there are several pending grants in this area.
Our other major clinical/translational research theme has been to characterize the process of vein bypass graft remodeling in humans, and the role of the inflammatory response. This is a multidisciplinary project that has involved investigators from surgery, cardiovascular medicine, and radiology. The goals are to develop a biomarker and imaging profile associated with increased risk for graft disease, and to determine the potential therapeutic implications. Our work has identified that inflammation is an important modulator of the early arterialization response following vein grafting. Current work in this program also seeks to determine the role of endothelial dysfunction in vein bypass healing and clinical outcomes. These projects have also been funded by NHLBI (HL075771, HL092163). Finally we have started a new multicenter project to determine genomic and proteomic markers of vascular healing in patients undergoing both open and endovascular interventions, funded by the non-profit research foundation Vascular Cures.