The work in our laboratory is focused on four areas:
- Identification of novel factor(s) that may aid in protection of myocardium
- Understanding of signals involved in homing of bone-marrow-derived stem cells to the heart
- Control of renin gene expression
- Gene therapy for cardiovascular diseases
Project 1: We are developing a preventive gene therapy strategy for myocardial protection from future ischemia/reperfusion (I/R) injury involving a single administration of a therapeutic gene with a vector system capable of efficient and long-term myocyte-specific and inducible expression of the therapeutic gene.
Project 2: Based on the hypothesis that specific signals are responsible for the homing and adherence of mesenchymal stem cells (MSCs) to myocardium and subsequent engraftment, we are identifying the chemical signals and adhesion receptors that mediate homing of MSCs to ischemic myocardium, enriching the MSC population that expresses receptors/ligands that mediate specific myocardial homing and to genetically modify these MSCs in order to enhance homing and adhesion to the ischemic myocardium.
Project 3: We are investigating the mechanisms of protection by genetically modified MSCs. We hypothesize that MSCs overexpressing Akt can secrete paracrine factors, which can confer cytoprotection, reduce apoptosis, and salvage myocardium. We are now in the process of identifying these factors, demonstrating their therapeutic potential either alone or in combination, and understanding the mechanism of cardiac protection and repair. In addition, we are cloning several novel genes with secretory protein products identified from the microarray studies performed with MSCs.
Project 4: The goals of this project are to identify co-localization of a nuclear hormone receptor family member (LXR) and renin in vivo, to understand consequences of juxtaglomerular cell-specific over expression and inhibition of LXR using genetically targeted mice, and understanding the consequences of disruption of CNRE in the renin gene. These experiments will define the role of LXR in renin regulation.
- Melo LG et.al. Gene therapy strategy for long-term myocardial protection using adeno-associated virus-mediated delivery of heme oxygenase gene.Circulation. 2002 Feb 5 ; 105(5): 602-7.
- Mangi AA et.al. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med. 2003 Sep; 9(9): 1195-201.
- Pachori AS et.al. Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury. Proc Natl Acad Sci U S A. 2004 Aug 17; 101(33): 12282-7.
- Gnecchi M. et.al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med. 2005 Apr; 11(4): 367-8.
- Morello F. et.al. Liver X receptors a and ß regulate renin expression in vivo. J Clin Invest. 2005 Jul; 115(7): 1913-22.
Victor J. Dzau, MD, Director
Zhiping Zhang, MD, PhD, Senior Research Scientist
Office: 4015 GSRB Building, Durham, NC
Campus mail: DUMC Box 3178, Durham, NC, 27710