Current Research and Scholarly Interests
I am now Chair of the Department of Cardiovascular Sciences in the Houston Methodist Research Institute (HMRI) in Houston, and the Director of the Center for Cardiovascular Regeneration in the Debakey Heart and Vascular Center. Our laboratory location is in the HMRI, a new (built in 2010) research facility (450,000 sq ft) housing a growing scientific community, with some outstanding investigators such as Neil Copeland and Nancy Jenkins, who are Nobel contenders for their work with the sleeping beauty transposon. I will be recruiting 13 faculty over the next 4 years to build the Department. It is going to be great fun, but I will miss this wonderful Stanford community. I will have some ongoing projects and collaborations here, that will keep me in touch with Stanford, facilitated by my new position as an Emeritus Professor at Stanford.
My Center for Cardiovascular Regeneration in Houston performs fundamental basic and translational work in cardiovascular regeneration from molecule to man. The goal is to transfer basic research insights into clinical trials using a vertically integrated approach with an array of biochemical and molecular tools, cellular and animal models, and clinical research techniques. Our mission is to to generate great ideas and transform cardiovascular care.
My own basic research is focused on induced pluripotent stem cells (iPSCs), as well as direct reprogramming, for vascular regeneration. We have discovered a critical role for activation of innate immune pathways in nuclear reprogramming to pluripotency, or in directed transdifferentiation. We have coined the term "transflammation" to describe the role of innate immune activation in epigenetic plasticity required for reprogramming (see Lee et al, CELL 2012).
We have a long-standing interest in two different pathways regulating endothelial function. Endothelium derived nitric oxide synthase(NOS) plays a critical role in EC survival, proliferation, and angiogenesis. There is an endogenous competitive inhibitor of the NO synthase pathway called ADMA (asymmetric dimethylarginine). We find that this molecule is elevated in disorders associated with endothelial dysfunction, and plays a significant role in causing vascular disease. ADMA becomes elevated in people with hypercholesterolemia, diabetes, and other vascular disorders. We find that oxidative stress impairs the activity of the enzyme (DDAH) that degrades ADMA. ADMA accumulates and blocks NO synthesis. Overexpression of DDAH (in our transgenic mouse or in endothelial cell culture) can reduce ADMA levels and increase NO synthesis, with significant consequences on vascular homeostasis and angiogenesis(Jacobi et al Circulation 2005).
We discovered a pathway modulating angiogenesis (Heeschen et al, Nature Medicine 2001). Nicotinic acetylcholine receptors on endothelial cells are upregulated with hypoxia, and when stimulated (by the endogenous transmitter acetylcholine), these receptors mediate endothelial tube formation in vitro, and angio
