The investigators' long term goals are to understand and prevent accelerated coronary artery disease following heart transplantation. Findings suggest that abnormal regulation and response to vascular smooth muscle growth factors may be important mechanisms leading to myointimal hyperplasia. Expression of the potent vascular smooth muscle growth factor, heparin binding acidic fibroblast growth factor (aFGF) is rapidly and dramatically increased in human hearts following transplantation, and both the number and functional type of FGF receptors are altered in the transplanted heart. Secreted isoforms of FGF receptor-1 (FGFR1) are present in normal hearts but are increased 30 to 50-fold in allografts. In contrast, transmembrane isoforms of FGFR1, are expressed only in allografts, predominantly during rejection episodes. Thus, events occurring during rejection, including production of IL-6 and TGF-B, modify the normal patterns of alternative MRNA splicing that control local expression of the FGFR1 gene. The investigators hypothesize that immunologic injury within the myocardium and in donor vessels leads to increased production of aFGF and enhanced response to this growth factor via expression of signaling isoforms of its receptor. To test this hypothesis, they will confirm that similar events occur in an inbred rat model of cardiac transplantation that results in vascular disease like human cardiac allograft vasculopathy (CAV); using the rat model, they will inhibit FGFR1 dependent signals by in-vivo transfection of an aFGF inhibitor and assess its efficacy in preventing the development of CAV. To facilitate the ultimate use of in vivo transfection in clinical transplantation, they will prospectively correlate the development of coronary intimal thickening in human cardiac allografts with expression of aFGF and isoforms of its receptors.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL053771-01A1
Application #
2231867
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1995-08-01
Project End
1999-07-31
Budget Start
1995-08-01
Budget End
1996-07-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Zhang, Qiwei; Fairchild, Robert L; Reich, Martha B et al. (2005) Inhibition of Src kinases combined with CD40 ligand blockade prolongs murine cardiac allograft survival. Transplantation 80:1112-20
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Miller, Geraldine G; Destarac, Luis; Zeevi, Adriana et al. (2004) Acute humoral rejection of human lung allografts and elevation of C4d in bronchoalveolar lavage fluid. Am J Transplant 4:1323-30
Kilkenny, Dawn M; Rocheleau, Jonathan V; Price, James et al. (2003) c-Src regulation of fibroblast growth factor-induced proliferation in murine embryonic fibroblasts. J Biol Chem 278:17448-54
de Haan, Gerald; Weersing, Ellen; Dontje, Bert et al. (2003) In vitro generation of long-term repopulating hematopoietic stem cells by fibroblast growth factor-1. Dev Cell 4:241-51
Byrd, Victor M; Kilkenny, Dawn M; Dikov, Michael M et al. (2003) Fibroblast growth factor receptor-1 interacts with the T-cell receptor signalling pathway. Immunol Cell Biol 81:440-50
Zhao, David Xiao-Ming; Hu, Yenya; Miller, Geraldine G et al. (2002) Differential expression of the IFN-gamma-inducible CXCR3-binding chemokines, IFN-inducible protein 10, monokine induced by IFN, and IFN-inducible T cell alpha chemoattractant in human cardiac allografts: association with cardiac allograft vasculopathy and J Immunol 169:1556-60
Zhao, X M; Hu, Y; Miller, G G et al. (2001) Association of thrombospondin-1 and cardiac allograft vasculopathy in human cardiac allografts. Circulation 103:525-31
Miller, G G; Davis, S F; Atkinson, J B et al. (1999) Longitudinal analysis of fibroblast growth factor expression after transplantation and association with severity of cardiac allograft vasculopathy. Circulation 100:2396-9
Byrd, V M; Ballard, D W; Miller, G G et al. (1999) Fibroblast growth factor-1 (FGF-1) enhances IL-2 production and nuclear translocation of NF-kappaB in FGF receptor-bearing Jurkat T cells. J Immunol 162:5853-9

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