Rokosh Lab Research Interests:
My lab focuses on G-protein coupled receptor signal transduction and the consequential regulation of cardiovascular function. While several receptors including muscarinic and alpha1 adrenergic, have been studied over the years, the lab has recently focused on the receptors for the chemokine, stromal cell derived factor 1a (SDF1), CXCR4 and CXCR7 and complement component C3 and their involvement in regulating cardiovascular function and response to injury. We are interested in how receptor activation modulates signal transduction and functional endpoints including cardiac performance, injury, and remodeling and regeneration after injury or stress. The broad expression of CXCR4, CXCR7, C3aR, C5aR, C5Lq results in complex regulation of several endpoint functions including cell survival, mobilization, chemotaxis, cell cycle, angiogenesis, and regeneration that are key elements in the etiology of cardiac pathophysiology.
We had identified SDF1 as an important survival factor and capable of protecting the myocardium from ischemia reperfusion injury (Hu et al. Circulation 2007) as well as being necessary in the myocardial response to injury (Dai et al. J Mol Cellular Cardiol 2010). These two early studies initially highlighted the importance of this ligand - receptor in the myocardial response to stress. However, we now find, using conditional CXCR4 and SDF1 knockout mice that CXCR4 and CXCR7 regulate multiple functions which have significantly changed how we perceive the receptor's contribution to the response to injury. The study of resident cardiac stem/progenitor cells showing SDF1 drives these cells into a quiescent state (Dimova et al. STEM CELLS 2013) is a good example demonstrating another important function this chemokine regulates and may confound regenerative potential with injury. Likewise, our studies of complement component C3 action in the context of myocardial remodeling after injury (Wysoczynski et al. STEM CELLS 2014) also suggest complex regulation of multiple functions. These studies have identified novel signaling and regulation during development and injury and include extensive regulation of miRNA networks. Studies are ongoing to understand how regulation of SDF1 and its activation of CXCR4 and CXCR7 and complement signaling mediate such actions in the heart and periphery and how they contribute ultimately to myocardial regeneration.
- Wysoczynski M, Solanki M, Dimova, N, van Hoose P, Brittian KR, Prabhu SD, Ratajczak MZ, and Rokosh G, 2014, Complement Component 3 is Necessary to Preserve Myocardium and Myocardial Function in Chronic Myocardial Infarction. STEM CELLS, May 8. doi: 10.1002/stem.1743. [Epub ahead of print]
- Dimova, N., M. Wysoczynski, and G. Rokosh, 2013, Stromal cell derived factor-1a promotes c-kit+ cardiac stem/progenitor cell quiescence through casein kinase 1a and GSK3b. STEM CELLS, Aug 23 doi 10.1002/stem.1534. [Epub ahead of print]PMID:24038789
- Luo, J., D. Obal, N. Dimova, and G. Rokosh. 2013, Cardiac myocyte-specific transgenic ecSOD target mitochondria to protect against Ca2+ induced permeability transition. Frontiers Physiology Oct 29; 4: 295.
- Madonna R, Bolli R, Rokosh G, De Caterina R. Targeting phosphatidylinositol 3-kinase-Akt through hepatocyte growth factor for cardioprotection. J Cardiovasc Med (Hagerstown). 2013 Apr;14(4):249-53.
- Madonna, R. and G. Rokosh, 2012, Insights into gene therapy for critical limb ischemia: the devil is in the details. Vasc. Pharm. May 8 Epub ahead of print.
- Madonna, R., R. Bolli, G. Rokosh, and R. De Caterina, 2012, Long-term engraftment and angiogenetic properties of lentivirally transduced adipose tissue-derived stromal cells. Molecular Biotechnology (Accepted) .
- Obal, D., S. Dai, R. Keith, N. Dimova, J. R.Kingery, Y-T.Zheng, J. L. Zweier, M.Velayutham, S. D. Prabhu, D. Conklin, A.Bhatnagar, R.Bolli, G. Rokosh, 2012, Overexpression of cardiomyocyte-specific extracellular superoxide dismutase increases nitric oxide bioavailability and reduces infarct size after ischemia/reperfusion. Basic Res. Cardiol. 107(6):305
- Bolli R, Chugh AR, D'Amario D, Loughran JH, Stoddard MF, Ikram S, Beache GM, Wagner SG, Leri A, Hosoda T, Sanada F, Elmore JB, Goichberg P, Cappetta D, Solankhi NK, Fahsah I, Rokosh DG, Slaughter MS, Kajstura J, Anversa P. 2011 Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet. 2011 Nov 26;378(9806):1847-57. Epub 2011 Nov
- Dai, S., F. Yuan, J. Mu, C. Li, N. Chen, S. Guo, J.R. Kingery, , S.D.Prabhu, R. Bolli, and G. Rokosh, 2010, Chronic AMD3100antagonism of SDF-1a-CXCR4 signaling exacerbates cardiac function and remodeling after myocardial infarctionJ. Mol. Cell. Cardiology 49(4):587-97.
- Wang G, Hamid T, Keith RJ, Zhou G, Partridge CR, Xiang X, Kingery JR, Lewis RK, Li Q, Rokosh DG, Ford R, Spinale FG, Riggs DW, Srivastava S, Bhatnagar A, Bolli R, Prabhu SD Cardioprotective and antiapoptotic effects of hemo oxygenase -1 in the failing heart. Circulation. 2010 May 4;121(17):1912-25. Epub 2010 Apr 19.
- Madonna, R., G. Rokosh, R. De Caterina, and R. Bolli, 2010, Hepatocyte growth factor/Met gene transfer in cardiac stem cells-potential for cardiac repair, Basic Res. Cardiol. 105:443-452.
- Tang, X-L.*, G. Rokosh*, S.K. Sanganalmath, F. Yuan, H. Sato, J. Mu, Q. Bi, S. Dai, C. Li, N. Chen, B. Dawn, G.Hunt,A. Leri, J.Kajstura, S. Tiwari, G. Shirk, P. Anversa, and R.Bolli, 2010, Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30-day old infarction Circulation 121: 293-305. *Co-first authors
- West, M.B*., G. Rokosh*,D. Obal, M. Velayutham, YT. Xuan, BG Hill, B. Dawn, R. Keith, J. Schrader, Y. Guo, D. Conklin, S.D Prabhu, J.L. Zweier, R. Bolli, and A. Bhatnagar, 2008, Cardiac Myocyte-Specific Expression of Inducible Nitric Oxide Synthase Protects against Ischemia/Reperfusion Injury by Preventing Mitochondrial Permeability Transition. Circulation 118:1970--8. *Co-first authors.
- Xiaofeng Hu, , Shujing Dai, , Wen-JianWu,Wei Tan, Xiaoping Zhu, Jingyao Mu, YiruGuo, Roberto Bolli, and G. Rokosh,2007,SDF-1a Confers Protection against Myocardial Ischemia/Reperfusion Injury: Role of the Cardiac SDF-1a–CXCR4 Axis, Circulation116:654-63.