Dr. Elissavet Kardami
Principal Investigator, Muscle Cell Biochemistry
Institute of Cardiovascular Sciences
Research Focus
(1) Characterization of the “injury-resistant” cardiac state:
We have established that the low molecular weight FGF-2 exerts a powerful protection of the rat heart from ischemia and reperfusion injury and dysfunction, even when administered after the onset of ischemia; the magnitude of protection is similar to that of preconditioning or post-conditioning manipulations. We are investigating the signal transduction mechanisms mediating FGF-2 cardioprotection. We have identified the gap junction protein connexin43, and its phosphorylation at specific sites, as a downstream target of FGF-2 signaling, and are now investigating their role in the induction as well as maintenance of protection.
(2) Cardiac Repair-Regeneration:
We have demonstrated that a single administration of low molecular weight FGF-2 during the development of myocardiac infarction induces results in substantial improvement in heart function and decrease in tissue loss both acutely and long-term. We are investigating the hypothesis that low molecular weight FGF-2 stimulates stem-cell based cardiac regeneration.
(3) Cardiac cell death – hypertrophy
We have discovered that the high molecular weight FGF-2 isoform causes cell death in an intracrine manner, and hypertrophy in an auto- or para-crine manner. We are investigating the mechanisms involved.
(4) Regulation of and by Connexin-43
We are investigating the role of connexin-43, the main cardiomyocyte gap junction protein, in the regulation of cardiomyocyte signaling relating to growth and gene expression. This project uses engineered Cx43 mutations and deletions to alter the properties of the molecule and is accompanied by proteomics studies to identify interacting partners of connexin-43 in the normal versus ‘stressed’ state.
Why is this work important?
Our work addresses fundamental issues in regards to the normal and pathological condition of the heart. Induction of cardioprotection and regeneration are very attractive and novel approaches aiming at reducing cardiac tissue loss and dysfunction and represent ‘hot’ research areas world-wide. Our work can identify means by which heart resistance to injury and cell death can be augmented. What techniques and equipment are used in this laboratory?
We are essentially a protein biochemistry and cell biology laboratory. Regular established techniques include cardiac cell isolation and culture, recombinant protein isolation, purification and analysis, protein detection, transient gene transfer, immunofluorescence, microscopy (regular and confocal), subcellular fractionation, in vitro and in vivo models of ischemic injury, isolated perfused rat heart approaches. We have standard cell biology – cell culture lab equipment.
About Elissavet Kardami:
E. Kardami obtained her Bachelor’s Degree in Biology, at the University of Athens, Greece (1975), and her PhD degree (1980) from the Department of Cell Biophysics, King’s College, London UK. She pursued post-doctoral studies at the Institute Pasteur, Paris, France and at Berkeley, University of California. She started her independent career as a Faculty member of the University of Manitoba, and a staff scientist at St. Boniface Hospital Research Centre in 1987. She is now a full professor in the Department of Human Anatomy and Cell Sciences, University of Manitoba, and a lab director (Muscle Cell Biochemistry) at the Institute of Cardiovascular Sciences, St. Boniface Research Centre. She is currently supervising 5 PhD students, one research associate, and one technician, and is funded by the CIHR and Heart and Stroke Foundation of Manitoba. She has published 73 peer-reviewed papers, and 10 book chapters to-date.
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Dr. Elissavet Kardami
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In Detail
Dr. Elissavet Kardami is studying how heart muscle cells respond to an injury stimulus, how they repair themselves after injury, and how the potential for subsequent cardiac failure can be prevented. She is tackling these issues by examining the activity of a growth factor protein normally present in the heart and throughout the body. “The growth factors are the molecules the body uses anyway, but they are somewhat suppressed in adults,” Dr. Kardami explains. “If we can subtly change their levels or properties to reactivate them, it may protect the heart’s health without many side effects.”
DIVIDE AND CONQUER – REGENERATING CELL GROWTH
After birth, heart cells stop dividing. As a person grows, the heart also grows, not through division but because the cells enlarge in size. This means that once heart cells become damaged, they cannot repair themselves as the cells of most other organs can – they are forever damaged.
Following a myocardial infarction, the amount of scarring that results from the injury will have a direct bearing on how well the remaining viable muscle tissue can function and how likely it is that the heart will subsequently go into failure. If this scarring could be reduced, heart function would be significantly improved. Dr. Kardami is studying how healthy cardiomyocytes can be stimulated to divide, replacing the dead muscle cells and thereby reducing the amount of scar tissue. Working with transgenic mouse models, Dr. Kardami’s laboratory is studying cardiomyocytes from different development stages to determine how signal transduction pathways are triggered by growth factors and their receptors. The lab is experimenting with various factors and combinations of factors to see whether cell division can be reactivated. While division of a fully differentiated adult cell has not yet been achieved, there are indications that certain combinations have the potential to succeed. Because these molecules are multi-functional, Dr. Kardami is working to genetically alter their structures in ways that will isolate the particular activity that stimulates cell division.
THE SELF-DEFENSE MOLECULE
A more immediate medical application for the growth factor Dr. Kardami is studying lies in its ability to protect cells during or immediately following a myocardial infarction. Because the protein appears to make cells and tissues more resistant to injury, the hypothesis is that if it is expressed in greater quantities in the heart, it can protect the organ from certain degrees of injury and improve its maintenance. Ideally, ways would be devised to stimulate the expression of the protein within the heart. However, Dr. Kardami speculates that, as a shortcut, the growth factor can be introduced into the patient’s circulatory system or into the myocardium itself upon arrival in the hospital or even en route to reduce the extent of cell destruction. The lab’s studies have confirmed that this is, in fact, the case in animal models. Recombinant technology makes production of sufficient quantities of the substance feasible for this application, and further developments surrounding the growth factor’s clinical potential are expected in the near future.
STUDYING COMMUNICATION GAPS
Another aspect of this laboratory’s studies involves the role of the same growth factor in the way heart cells communicate. In order to act as an efficient pump, the heart’s many muscle cells must contract in simultaneous fashion. This coordination is made possible by channels (termed gap junctions) between cells and the passage of a variety of small molecules (signals) through gap junctions. Abnormalities in gap junction proteins are linked to arrhythmias. The growth factor protein plays a role in determining the size and function of the channels and the number and type of molecules that move through them at any time. This indicates that growth factors also have a role in arrhythmias. These studies are currently being conducted at the cell culture and whole heart level.
NEW FRONTIERS
It is only recently that regenerating heart muscle cells was believed to be impossible. Advancements in cell and molecular biology have revealed a greater complexity and, with that complexity, hope that damage does not have to be irreversible. The next challenge in the competitive field of study will be to determine whether the human heart will respond in the same way as animal models.
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