Basic Research on site facilities for: cardiac catheterization and electrophysiology, biochemical assays, tissue and cell culture, gene transfer, evaluation of gene transfer expression, cell transplantation, and animal care.
Senior Investigators:
Research projects that are currently under investigation at the institute include:
Genetic modulation, cell transplantation and tissue engineering promise a revolutionary approach for myocardial regeneration and tissue repair after myocardial injury. Current data derived from animal models suggest that it may be possible to treat heart failure by inserting genetic materials or myogenic cells into injured myocardium. Success with animal models has raised the hope for new treatment after heart attacks and could prove an alternative to transplantation, particularly in elderly patients for whom there is often a lack of donor hearts.
Cell transplantation is a promising strategy to increase viability and augment ventricular function after myocardial infarction. Cells subjected to genetic modification could also be used for the long-term delivery of therapeutic recombinant proteins to the heart providing an alternative strategy for gene therapy.
Stem cells are a unique population of cells characterized by their pluripotency, i.e., the ability to differentiate into multiple cell lineage. Stem cells are unlimited in number since they have self-regenerating capacity and can be expanded in vitro. For these reasons, stem-cell based therapy for cardiac muscle regeneration has been under intense research and progress. The purpose of our research is to test various cell sources, including embryonic and adult stem cells, for cell-based therapy of myocardial diseases.
Tissue engineering is a relatively new discipline that combines isolated functioning cells and biodegradable three dimensional (3-D) polymeric scaffolds. Tissue engineering facilitates the creation of new functional tissue that replaces lost or failing tissue. This scaffold temporarily provides the biomechanical support for cells until they are able to produce their own extracellular matrix. The potential additional advantage of such tissue engineering over the isolated cell transplantation approach, is improved control of the tissue formation process, of the graft shape and size, and of the ability to determine the consistency of the graft (e.g. number of cells, cell to cell ratio). Optimization of the scaffold and techniques for cell manipulation in culture will further encourage these cells to express their inherent biological potential to form differentiated tissue. Recent advances in methods of cardiomyocyte isolation and 3-D culture, show promise and will contribute to cardiac tissue engineering in vitro. The purpose of our research is to develop new scaffolds and to test various cell sources for in vivo cardiac tissue engineering.
Gene transfer offers new therapies for the infarcted myocardium. The ability to introduce recombinant transgenes that encode therapeutic proteins into the infarcted myocardium may stimulate new vessel formation, accelerate healing and enhance myocardial performance. Today, it is even possible to consider genetic modulation leading to regeneration of myocytes within the infarcted myocardium. One of the most attractive goals in the field of gene therapy for myocardial infarction and heart failure is genetic modulation in situ, leading to regeneration of new contractile tissue after myocardial damage. One possible route to muscle regeneration is to force the fibroblasts in the healing heart lesions to differentiate into muscle. At present, there is insufficient knowledge about cardiac muscle determination and differentiation to induce cells to form myocardium. However, much more is known about skeletal muscle differentiation. In skeletal muscle, the muscle-specific MyoD family of transcription factors is able to prompt the skeletal muscle differentiation program in a variety of cells including fibroblasts. Transformation of cardiac fibroblasts in the scar of myocardial infarction into skeletal myocytes could add to myocardial contractility. Our research shows that it is possible to exploit the unique capacity of MyoD to activate myogenesis in cardiac fibroblasts ex vivo and to create a vast source of autologous myogenic cells for transplantation.
Physical fitness and exercise training are known protective factors against cardiovascular morbidity and mortality. In our laboratory we have shown that swimming exercise training prior to acute myocardial infarction significantly improve myocardial function (assessed by echocardiography) and reduce scar size (assessed histologically) during the healing phase post infarction. We further investigate the role of exercise-induce neovascularization as a protective mode following ischemic injury as well as the molecular changes associated with chronic exercise training (microarrays gene chips techniques).
Selective drug delivery has been the focus of researchers, clinicians, and pharmaceutical companies for many decades, however, with minimal success. The benefits of improving drug delivery and targeting techniques include:
- the use of lower dosages thus leading to lower cost/ expenses.
- less untoward effects.
- lower toxicity.
- higher patient's compliance. Our research hypothesis for the improvement of local, selective drug delivery is based on the use of external magnet - to trap ferromagnetic particles (as drug carriers), and focused ultrasound (US) - for activation of compounds incorporated within the particles, at the territory of interest.
Impaired tissue perfusion is a major cause of acute infarction, organ dysfunction, muscle injury and diabetic foot ulcers that lead to limb amputation. Restoration of blood supply depends on spontaneous or mediated angiogenesis, which is a culmination of molecular and cellular processes required to generate new blood vessels. The goal of our research is to develop a new, noninvasive therapeutic technology for restoration of blood supply to ischemic tissues using therapeutic ultrasound.
PolyADP-ribosylation is a fast transient post-translational modification of nuclear proteins, which is catalyzed mainly by PARP-1. This most abundant and highly conserved chromatin-bound protein is intensively activated by nicked DNA. However, we have recently discovered that PARP-1 is also a target for signal transduction under normal conditions. PARP-1 is rapidly and transiently activated by electrical stimulated in rat brain cortical neurons in the absence of DNA damage (Homburg et al., J. Cell Biol. 150:293-307 [2000]). In our present research we investigate signal transduction mechanisms mediating the activation of PARP-1 and In view of these findings we examine the physiological roles of this intriguing fast activation of PARP-1.
PARP-1 is activated in sensory neurons of Aplysia Californica by stimulations evoking long-term facilitation in their sensory-to-motor synapses. We examine a novel molecular mechanism associating memory formation with DNA-transcription via polyADP-ribosylation
We examine signal-induced activation of PARP-1 in cultured cardiomyocytes. Signal-induced polyADP-ribosylation of transcription factors may underlie disease states as ischemia-reperfusion myocardial hibernation, cardiac hypertrophy, heart failure and myocyte apoptosis.
Research projects are conducted in collaboration with other local and international research institutes, technological and industrial companies. The investigators include physicians, physiologists and other scientists from related areas.
The institute provides an excellent environment for M.Sc., Ph.D, basic science and final projects for medical and non-medical students in the area of cardiovascular biology
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Myocardial Regeneration