- Dr. Anette Melk, Principal Investigator
- Children’s Hospital, Medical School Hannover. Hannover, Germany
- Overcoming Senescence Mechanisms Will Lead to Better Renal Graft Survival
The survival of transplanted kidneys is shorter than the expected survival of the organ donor. This is due to many stresses that occur during the transplantation process (e.g. duration of ischemia, rejection episodes, hypertension). The histological picture of such a damaged organ resembles the features of a normally aged old kidney. This is especially true for so called "marginal donor kidneys" that are considered suboptimal because of older donor age, pre-existing hypertension or long ischemia time. Unfortunately, the use of such donor kidneys has dramatically increased due to high number of patients and the resulting organ shortage. Somatic cellular senescence (SCS), a phenomenon described for cells in culture, can be reached through telomere-dependent and -independent pathways. In our previous work we found that features of SCS are strongly associated with kidney aging, are induced by peri- and post-transplant stresses and are detectable in biopsies from transplants with long-term failure. One caveat of all studies in animal models with regard to SCS is the fact that normal laboratory mice do not use telomere-dependent SCS pathways.
The aim of this project is: 1) to show the suitability of a particular mouse strain, the telomerase (Terc) knock-out mouse, in which both SCS pathways are active, to resemble the situation in old donor kidneys; 2) to study so far experimental strategies that overcome SCS, and 3) to evaluate already clinically used drugs for their effect on SCS. If we were able to define ways of interfering with SCS that lead to superior graft survival, this would allow for the development of new therapeutic approaches, especially with regard to marginal donor transplantation.