Research Project
6735776
[unreadable] DESCRIPTION (provided by applicant): [unreadable] Organ transplantation remains the only available therapy for end-stage disease, thus a large donor pool is deemed essential to satisfy the current clinical organ demand. The use of hypothermia for isolated organ preservation has been proven an effective method for the protection of cells and tissues. Acid-base regulations an important determinant of cell survival after exposure to ischemia, therefore pH regulation during hypothermic preservation is crucial for optimal tissue and organ survival following cold ischemic storage. The major goal of this study is to determine, at the cellular level, the role of solution relative buffer capacity in providing the appropriate pH environment and the needed acid-base regulation during low temperature storage, with the ultimate goal of designing a high quality, more efficient organ preservation solution. This study will test the hypothesis that buffer solutions characterized at low temperature by high buffer efficiency will provide the best cytoprotection during cold ischemia. These solutions will be tested for the preservation of isolated adult cardiomyocytes, for various time periods under profound hypothermic conditions. Cardiomyocyte contractile function, intracellular calcium dynamics and pH will be measured post-preservation while the cells will be electrically stimulated in a normothermic physiological environment. Cells metabolic activity and apoptotic injury will be assessed post-preservation. The storage solution chemistry will be correlated with the cardiomyocyte mechanic and metabolic functions post preservation, to determine the buffer and buffer efficiency that provide the best cardiomyocyte protection for prolonged period of cold storage. This will result in submission of Phase-II that will be designed to optimize the buffer characteristics of the myocardial preservation solution, by determination of the best buffer compounds and their optimum concentration on the basis of isolated myocyte survival physiology, and to confirm the efficacy of the optimized solution for the extended preservation of the whole heart in a working heart transplant model. [unreadable] [unreadable]
