Research & Publications
Our goal is to understand how vascular smooth muscle cells contribute to normal vessel function and to cardiovascular disease. Hyperproliferation or dysfunction in vascular smooth muscle cells contributes to atherosclerosis, organ transplant failure, and failure of revascularization therapies such as balloon angioplasty or bypass surgery. By understanding the regulatory mechanisms of vascular smooth muscle, we aim to develop new therapies for treatment and prevention of cardiovascular diseases.
Specialized Terms: Vascular smooth muscle; Differentiation; Signal transduction; Transcription; Epigenetics
Extensive Research Description
Brief Research Summary
Our studies are aimed at understanding the molecular mechanisms that regulate vascular smooth muscle cell (SMC) phenotype. Mature SMC retain the ability to de-differentiate and re-enter the cell cycle. This is essential for such processes as angiogenesis, but also contributes to the pathogenesis of atherosclerosis, intimal hyperplasia, and restenosis.
Regulation of Vascular Smooth Muscle Phenotype: Rapamycin-eluting stents have revolutionized treatment of coronary artery disease, dramatically reducing restenosis. While highly efficacious in this localized drug delivery setting, systemic high dose rapamycin is not a viable strategy for other vascular diseases due to adverse effects. Our goal is to understand the molecular mechanisms by which rapamycin beneficially affects SMC phenotype, in order to develop novel therapeutics. Identifying the smooth muscle-specific targets of the mTOR pathway may generate new therapeutic strategies for treatment and prevention of atherosclerosis and intimal hyperplasia.
Epigenetic regulation: We have discovered that the mTOR pathway promotes VSMC differentiation through regulation of the DNA modifying enzyme TET2. We have identified TET2 as a novel master epigenetic regulator of VSMC phenotype. Notably, TET2 promotes changes in chromatin that lead to expression of prodifferentiation genes including SRF and myocardin and contractile genes such as SM-MHC and SM-alpha actin, while concomitantly downregulating expression of de-differentiation-associated genes including KFL4. We are currently employing genome-wide epigenetic methods to investigate mechanisms by which TET2, histone acetyltransferases, and other epigenetic regulators coordinately remodel chromatin to allow for VSMC plasticity.
Cardiology; Cardiovascular Diseases; Pharmacology; Vascular Diseases; Signal Transduction