Progenitor cell transfer for functional repair in ischemic cardiomyopathy in pigs (C. Dubois, X. Liu)
This project is directed at studying the capacity of different progenitor cell populations in enhancing functional repair after myocardial infarction in pigs. The experimental model closely mimics the clinical condition in patients with post-infarction heart failure and allows comparative studies of cell transfer methods, dose-response relations using surrogate endpoints, and multi-modal, state-of-the-art imaging technology including PET-CT and MRI.
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Targeted strategies to enhance homing and engraftment of progenitor cells in the ischemic dysfunctional myocardium (X. Liu, O. Gheysens, P. Pokreisz)
This project is directed at studying targeted interventions to enhance the engraftment and survival of transferred progenitor cells in the ischemic, dysfunctional heart. The interventions will focus on strategies to enhance resistance of progenitor cells to ischemic cell death as well as on strategies that improve homing to the target organ. Special attention will be given to the role of NO-cGMP signaling in these processes because we found that inhaled NO can decrease microvascular obstruction in the hearts of pigs with cardiac ischemia-reperfusion (I/R) injury [Liu et al. J Am Coll Cardiol. 2007;50:808-17]. Improved microvascular function may augment the therapeutic efficacy of exogenous or endogenous progenitor cells. We will use bone marrow transplantation models and multi-modal small animal imaging techniques, including bioluminescence, PET-CT, and MRI, to characterize the role of NO signaling in modulating the response to cardiac injury of both exogenous and endogenous progenitor cells, particularly in the context of diabetes mellitus and atherosclerosis. |
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Role of NO-cGMP signal transduction in cardiomyogenesis and cardiac resident cells in health and disease (O. Gheysens, P. Pokreisz, X. Liu)
This project is directed at studying the role of NO in cardiomyogenic differentiation of stem cells and in augmenting the regenerative response to cardiac injury. Mice with cardiac-specific NOS3 over-expression, have improved LV function and better survival after MI. The beneficial effects of increased cardiac NO levels are associated with increased DNA synthesis in the remodeling left ventricle. We propose to use in vitro studies in isolated cardiac resident cells from wild-type and NOS3-transgenic mice as well as in vivo studies where these cells will be used for direct intramyocardial injection in mice after myocardial infarction. |
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Role of phosphodiesterase-5 in the pathophysiology of clinical heart failure and in murine models of cardiovascular disease (S. Vandenwijngaert, P. Pokreisz)
This project is directed at studying the role of NO-cGMP-PDE signal transduction in the heart and in isolated cardiomyocytes of wild-type and transgenic mice with cardiac-restricted overexpression of PDE5. We will study the role of PDE5 gne function at baseline and after left and right ventricular pressure overload, induced by hypoxic pulmonary vasocontriction and transverse aortic constriction. At the same time, we will investigate the expression of PDE5 in the heart of patients with different stages of cardiomyopathy and heart failure severity. |
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Placental growth factor transfer for chronic ischemic cardiomyopathy (X. Liu)
This project is directed at studying the capacity of recombinant Placental Growth Factor (PlGF) delivery to enhance collateral vessel development and thus nutrient perfusion to ischemic dysfunctional myocardium in pigs. Chronic reduction in perfusion in a vascular territory results in impaired systolic and diastolic function and a decline in global and regional ejection fraction, as evidenced by invasive hemodynamic measurements, MRI and colored microsphere analysis. The effect of PlGF will be compared to placebo infusion of vehicle in a randomized blinded study using MRI and microsphere technology to evaluate functional recovery. |
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Induced pluripotent stem cells: a novel disease model for hereditary cardiomyopathy in end-stage heart failure (A. Patel)
The aims of this project are to generate induced Pluripotent Stem Cells from differentiated human somatic cells, obtained from patients with hereditary cardiomyopathy, to study directed differentiation from human iPS into cardiomyocytes and to phenotype differentiated human cardiomyocytes, as a novel disease model. |
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Research 
