Transgenic Rabbits

For the last several decades, advances in molecular genetics facilitated the development of transgenic and gene-ablated (knock-out) animal models as described above. This technique has been used extensively to elucidate the role of various proteins in the heart. However, these studies have been mainly limited to the mouse and findings in murine species cannot be always generalized to higher mammalian species. Our studies on phospholamban ablation and overexpression in the mouse have yielded significant insights into the role of this protein in cardiac function.

Phospholamban is a key determinant of myocardial contractility and the ß-adrenergic responses. Increased phospholamban levels or activity are deleterious to the heart and lead to heart failure. Furthermore, we have discovered that decreasing phospholamban activity, either by phosphorylation or down-regulation, is very beneficial to the heart. However, the majority of our studies have been performed in murine models, and sarcoplasmic reticulum (SR) calcium cycling is different between rodents and larger mammalian species, such as the rabbit and the human. Thus, we wish to rigorously extend our analysis of the role of phospholamban to the rabbit heart in collaboration with Dr. J. Robbins, University of Cincinnati Children's Hospital Research Foundation.

The rabbit exhibits a larger heart and slower heart rate than the mouse. In addition, the rabbit heart expresses the slow ß-myosin heavy chain isoform (MyHC), similar to the human heart, and its calcium cycling characteristics are similar to those of the human heart. Specifically, the rabbit and human heart share a major similarity in their reliance on SERCA and the Sodium-Calcium Exchanger (NCX) for the extrusion of calcium during diastole: they rely on SERCA to remove ~70% of the calcium and the NCX for 28%. In contrast, rodents, which exhibit much higher heart rates, rely on SERCA for ~90% of calcium extrusion and the NCX only extrudes 8%. All in all, the murine heart and the human heart are quite dissimilar and further therapeutic applications of our knowledge of phospholamban and the SR, require that we extend our studies to larger species, such as the rabbit. The power of the rabbit system is its ability to confirm or disprove testable hypothesis directed at potential human therapeutic approaches.

Our main objectives are to determine the role of SR calcium handling and specifically, phospholamban, the inhibitor of SERCA2, in the normal and failing rabbit heart by generating transgenic rabbit models.