Mechanismus regulating the functional expression of the antiapoptotic protein survivin in tissue hypoxia and reperfusion

• Antragsteller: Dr. Axel Menzebach
• Fachliche Zuordnung: Anästhesiologie
• Förderung: Förderung von 2003 bis 2004
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 5410030

Annually up to 750.000 Americans require cardiopulmonary resuscitation (CPR) after cardiac arrest (CA)1. About 30% reach the hospital, while only 14% are ultimately discharged. A large proportion of deaths are associated with the "post-resuscitation" syndrome, characterized by multi-organ damage2. Impaired renal function plays a critical role in reperfusion injury and contributes to the poor prognosis of these patients. Therefore, acute renal failure (ARF) continues to remain a clinical dilemma as mortality and morbidity have been unchanged over the past several decades despite advances in technology. Even modest degrees of acute renal failure not necessitating dialysis, increase the risk of death for critically ill patients approximately fivefold3. Despite intensive investigation into the pathophysiology of ARF, there has been  remarkably little translation into effective therapeutic strategies. Apoptosis is a physiological form of cellular death in which cells turn-on an intrinsic genetic program that leads to their destruction in a highly regulated manner. In the kidney, Fas receptor mediated apoptosis has been implicated in the pathogenesis of several diseases, including ischemic or toxic acute tubular necrosis (ATN), and is thought to contribute to the renal4 dysfunction in ARF. Survivin belongs to the family of genes known as inhibitors of apoptosis proteins (IAP), which are important in regulating Fas ligand-induced renal apoptosis, hepatocellular damage and vascular injury5,6. We hypothesize that regulation of survivin expression may modulate kidney damage following ischemia and reperfusion. The goal of this proposal is to elucidate the in vivo and in vitro role of survivin following tissue hypoxia and reperfusion in the kidney. This will be accomplished by utilizing transgenic mouse models and cell lines to evaluate key molecular events, which regulate apoptosis in the kidney. These studies will hopefully provide new insights into the pathogenesis of ATN, and lead to the development of novel therapeutic and preventive approaches.

• DFG-Verfahren: Forschungsstipendien