One lab in the Department of Cardiovascular and Thoracic Surgery has been investigating cardiac metabolism under conditions relevant to open heart surgical procedures, such as after ischemia and during cardioplegic arrest. Investigators have identified changes in substrate utilization patterns in cardiac tissue that occur as a result of potassium cardioplegia and hypothermia, and have investigated a variety of substrate modifying agents that lead to improved cardiac performance after ischemia.
Substrate Metabolism in the Lung
Studies of substrate metabolism in the lung have also been conducted with a goal of improving lung preservation strategies for transplantation.
Long-Term Heart Preservation
We have several studies focused on long-term heart preservation for transplantation using a device that provides continuous perfusion to the stored organ.
Role of Thymosin in Cardiac and Neuronal Tissue Regeneration and Repair
Our additional basic science research group, located at the Department of Molecular Biology, evaluates the biological and molecular role of thymosin ß4 (TB4), a 43 amino acid secreted peptide, on cardiac and neuronal tissue regeneration and repair in adult mammals. We demonstrated that TB4 inhibits myocardial cell death and initiates coronary regrowth,while activating various progenitors in the heart.
Systemic administration of TB4 resulted in increased cardiac function after ischemia. We discovered that the derivatives of TB4 might have similar regenerative effects on adult organs. We developed various in vitro embryonic and adult progenitor cell culture assays and in vivo pathological rodent models applicable to analyze the molecular and physiological effects of chemically synthesized molecules in a high throughput biological screen.
To understand the molecular mechanisms responsible for post-ischemic tissue repair, we apply cDNA and microRNA microarrays in animal and human tissue samples to determine novel therapeutic candidates and mechanisms of action. We intend to link animal investigations with human applications by testing the physiological and molecular effects of highly purified peptide candidates in human pre-transplantation patients at the time of ventricular assist device implantation.
To further expand our horizons, we initiated investigations that analyze the effect of TB4 and other small peptides during tumor generation in various animal models. Our worldwide collaborations with numerous leading scientists of the cardiac field include C. Kupatt (Germany), P. Riley (England), B. Sumegi (Hungary), K. Fukuda, O. Nakagawa, and H. Yamagishi (Japan).
Controlled Drug Delivery to the Heart
One of the focuses of our basic science research is controlled drug delivery to the heart. Many novel therapeutic molecules are challenging to administer, due to undesirable systemic effects, short half-life in the blood, or where multiple interventions are impractical. Implantable biodegradable matrices for prolonged release of drugs show promise in overcoming these obstacles. We synthesize and test excipient molecules designed to improve the controlled release implant.
These molecules are designed to influence drug release kinetics, as well as protect the drug while residing in the controlled release matrix. This technology can be applied to many therapeutics and their relevant diseases.
Our microsurgery lab is experienced in generating and analyzing models of heart disease in the mouse. Mouse surgeries, although difficult, have the distinct advantage of higher throughput, lower costs per animal, and especially the ability to study the vast number of transgenic and knock-out mice already available. We are capable of performing myocardial infarction by coronary artery ligation, left- and right-sided heart failure via banding of the aorta, and pulmonary arteries, respectively, and hind limb motor nerve stimulation by pacer implantation.
After surgery, we utilize echocardiography to measure functional changes in the mouse heart. This component of our research was integral to the discovery of the cardio-protective effects of the peptide thymosin beta-4. We also performed surgeries that contributed to determining the role of myocardin-related transcription factor A in controlling scar tissue formation in ischemic heart disease.