This represents a competing renewal application to study gene transfer as a means to alter the function of transplanted hearts. Cardiac transplantation is limited by the limited supply of donor hearts and perioperative ventricular dysfunction. Ventricular dysfunction (including RV dysfunction due to recipient pulmonary hypertension) and allograft vasculopathy are major causes of cardiac transplant failure. Understanding signaling mechanisms may be important to improve graft function and survival. Signaling through G-protein coupled receptors (GPCR), especially BAR, is important for normal cardiac and vascular smooth muscle cell physiology. BAR signaling is often compromised in the transplanted human heart, and several agents implicated in allograft vasculopathy can signal through G proteins. Transgenic mice have been developed with altered BAR and G protein signaling, including mice in which BAR-kinase (BARK1) is overexpressed. Increased expression of a BARK1 inhibitor improves cardiac performance in heart failure and transplant models. The plans are to use viral-mediated gene transfer in rat and rabbit models and transgenic mice models to investigate mechanisms by which GPCR signaling affects graft function.
The Aims are (1) to characterize BAR signalling in brain dead rabbit hearts and to try to improve function with adenoviral delivery of BAR signalling/inhibitory molecules; (2) to characterize BAR signalling and elucidate molecular defects in murine cardiac grafts, to use transgenic BAR signaling mutants to determine effects on graft function, and to use a rabbit model of heterotopic cardiac transplantation to study the effects of acutely manipulating BAR signalling; (3) to use a pulmonary artery banding model in rabbits to produce RV stress, as a condition to test BAR signalling and as a means to improve posttransplant RV dysfunction; and (4) to study the role of G protein signalling in mediating vascular smooth muscle (VSM) cell proliferation, and to use a rat aortic allograft model to test strategies to limit VSM hyperplasia in transplantation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL059533-07
Application #
6830476
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Bridges, Nancy D
Project Start
1998-01-01
Project End
2004-12-31
Budget Start
2003-09-01
Budget End
2003-12-31
Support Year
7
Fiscal Year
2003
Total Cost
$137,234
Indirect Cost
Name
Thomas Jefferson University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Bathgate-Siryk, Ashley; Dabul, Samalia; Pandya, Krunal et al. (2014) Negative impact of ?-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms. Hypertension 63:404-12
Lymperopoulos, Anastasios; Rengo, Giuseppe; Koch, Walter J (2013) Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ Res 113:739-53
Boucher, Matthieu; Pesant, Stephanie; Lei, Yong Hong et al. (2008) Simultaneous administration of insulin-like growth factor-1 and darbepoetin alfa protects the rat myocardium against myocardial infarction and enhances angiogenesis. Clin Transl Sci 1:13-20
Pleger, Sven T; Harris, David M; Shan, Changguang et al. (2008) Endothelial S100A1 modulates vascular function via nitric oxide. Circ Res 102:786-94
Hata, Jonathan A; Williams, Matthew L; Schroder, Jacob N et al. (2006) Lymphocyte levels of GRK2 (betaARK1) mirror changes in the LVAD-supported failing human heart: lower GRK2 associated with improved beta-adrenergic signaling after mechanical unloading. J Card Fail 12:360-8
Pleger, S T; Most, P; Heidt, B et al. (2006) S100A1 gene transfer in myocardium. Eur J Med Res 11:418-22
Tevaearai, Hendrik T; Walton, G Brant; Keys, Janelle R et al. (2005) Acute ischemic cardiac dysfunction is attenuated via gene transfer of a peptide inhibitor of the beta-adrenergic receptor kinase (betaARK1). J Gene Med 7:1172-7
Pleger, Sven T; Remppis, Andrew; Heidt, Beatrix et al. (2005) S100A1 gene therapy preserves in vivo cardiac function after myocardial infarction. Mol Ther 12:1120-9
Kettlewell, S; Most, P; Currie, S et al. (2005) S100A1 increases the gain of excitation-contraction coupling in isolated rabbit ventricular cardiomyocytes. J Mol Cell Cardiol 39:900-10
Most, Patrick; Boerries, Melanie; Eicher, Carmen et al. (2005) Distinct subcellular location of the Ca2+-binding protein S100A1 differentially modulates Ca2+-cycling in ventricular rat cardiomyocytes. J Cell Sci 118:421-31

Showing the most recent 10 out of 38 publications