Cardiovascular disorders continue to lead national morbidity, mortality, and cost figures. Neointimal hyperplasia stands as the underlying pathophysiology of many of these disorders. Inflammation has been associated with neointimal hyperplasia and the related process of atherogenesis, although it remains uncertain whether arterial remodeling occurs by way of inflammatory dependent mechanisms, or whether the inflammation is a secondary event. The current proposal details a research and training program that combines didactic courses, quality interactions with established investigators, and a hypothesis driven mechanistic research plan. Additionally, it provides new training in cytokine biology, advanced immunohistochemistry methods and gene therapy approaches. The grant has been thoughtfully constructed to help the Principal Investigator reach his long-term career goal of independent investigatorship as an academic vascular surgeon and to simultaneously advance our understanding of the mechanisms of neointimal hyperplasia. The overall scientific hypothesis of this training program is that neointimal hyperplasia proceeds by way of inflammatory dependent mechanisms. In this project we will dissect the roles of the pro-inflammatory cytokine TNF-alpha, and the anti-inflammatory cytokine IL-10, in neointima formation. Preliminary studies in a murine model suggest absence of biologically active TNF-alpha results in ten-fold less neointima formation. The chronology and cellular mediators (leukocytes and smooth muscle cells) of this TNF-alpha effect are unknown, and will be defined in this study. Because TNF-alpha can signal through two distinct receptors, TNFRI (P55) and TNFRII (p75), we will ascertain (using a genetic approach) through which receptor is TNF-alpha signaling accomplished in the setting of arterial remodeling. We hypothesize that endogenous TNF- alpha chronically upregulates neointimal hyperplasia through enhanced artery wall inflammation by way of signaling through the p55 receptor. IL-10 is an anti-inflammatory cytokine that stands as a primary endogenous downregulator of TNF-alpha. Preliminary studies suggest that delivery of viral IL-10 by way of gene therapy approaches attenuates neointimal hyperplasia. Using genetic, pharmacologic, and gene therapy approaches we will determine if neointimal hyperplasia is modulated by IL-10 dependent mechanisms, and the cellular events by which this sequence proceeds. We hypothesize that Ill-10 downregulates neointimal hyperplasia. TNF-alpha and IL-10 mediated cellular processes serve as a potential site for therapeutically interrupting pathologic arterial remodeling.
| Mauro, Christine R; Ilonzo, Godfrey; Nguyen, Binh T et al. (2013) Attenuated adiposopathy in perivascular adipose tissue compared with subcutaneous human adipose tissue. Am J Surg 206:241-4 |
| Jiang, Zhihua; Tao, Ming; Omalley, Kerri A et al. (2009) Established neointimal hyperplasia in vein grafts expands via TGF-beta-mediated progressive fibrosis. Am J Physiol Heart Circ Physiol 297:H1200-7 |
| Berceli, Scott A; Tran-Son-Tay, Roger; Garbey, Marc et al. (2009) Hemodynamically driven vein graft remodeling: a systems biology approach. Vascular 17 Suppl 1:S2-9 |
| Jiang, Zhihua; Yu, Peng; Tao, Ming et al. (2009) Interplay of CCR2 signaling and local shear force determines vein graft neointimal hyperplasia in vivo. FEBS Lett 583:3536-40 |
| Jiang, Zhihua; Yu, Peng; Tao, Ming et al. (2007) TGF-beta- and CTGF-mediated fibroblast recruitment influences early outward vein graft remodeling. Am J Physiol Heart Circ Physiol 293:H482-8 |
| Berceli, Scott A; Jiang, Zhihua; Klingman, Nina V et al. (2006) Early differential MMP-2 and -9 dynamics during flow-induced arterial and vein graft adaptations. J Surg Res 134:327-34 |
| Fernandez, Chessy M; Goldman, Darin R; Jiang, Zhihua et al. (2004) Impact of shear stress on early vein graft remodeling: a biomechanical analysis. Ann Biomed Eng 32:1484-93 |
| Jiang, Zhihua; Wu, Lizhen; Miller, Brett L et al. (2004) A novel vein graft model: adaptation to differential flow environments. Am J Physiol Heart Circ Physiol 286:H240-5 |
| Jiang, Zhihua; Berceli, Scott A; Pfahnl, Chun L et al. (2004) Wall shear modulation of cytokines in early vein grafts. J Vasc Surg 40:345-50 |
| Jiang, Zhihua; Berceli, Scott A; Pfahnl, Chun L et al. (2004) Impact of IL-1beta on flow-induced outward arterial remodeling. Surgery 136:478-82 |
Showing the most recent 10 out of 11 publications
