Project Details
Projekt
Deciphering the Role of Heme as a DAMP in Renal Ischemia-Reperfusion Injury
Applicant
Dr. Tristan Wagner
Subject Area
General and Visceral Surgery
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 572479455
As the prevalence of diabetes and arterial hypertension are rising, resulting chronic kidney insufficiency has become the ninth leading cause of death worldwide. Though other options are available kidney transplantation remains the preferred renal replacement therapy, since it is associated with significantly improved long term survival and superior quality of life. Due to organ shortage, the key challenges in modern transplant-medicine are successful immediate and long-term graft function of marginal organs. In this context ischemia reperfusion injury (IRI), causing a sterile inflammation in donated organs, is a major risk factor. The underlying mechanisms of renal IRI, which primarily happens in the proximal tubular cells, are to this day not fully understood. Previous data show that heme, a potent Danger associated molecular pattern (DAMP) molecule, play a crucial role in cardiac IRI. The Otterbein Lab and I suppose that heme and its signaling pathways are also an important trigger of renal IRI, through activating the innate and adaptive immune system, causing oxidative stress, cell death and therefore resulting in impaired graft-function. This project aims to resolve three resulting questions: First, the role of heme as a DAMP will be deciphered in renal tubular cells using a rodent in-vivo renal IRI model. Second, the contribution of the main receptor through which heme binds and signals (Toll-like-Receptor 4) will be elucidated using knock out mice in the in vivo renal IRI model. Third, we want to demonstrate that excess heme and heme -related pathways in renal IRI are a modifiable factor through integrating caloric restriction as a treatment option. Caloric restriction has substantial protective effect in models of renal IRI and is known to promote organ protection in humans. Lastly, I want to correlate my findings with human bio samples obtained from the DILKID trial. This interventional, randomized controlled trial is based in Cologne and studies the nephroprotective effects of caloric restriction in kidney transplant patients. As a visceral surgeon, who primarily focuses on transplant surgery, I have previously worked on projects to visualize reperfusion dynamics during kidney and liver transplantation. My research proposal “Deciphering the Role of Heme as a DAMP in Renal Ischemia Reperfusion” complements my previous work by shifting to underlying pathogenic mechanisms. The aim of the proposed project is to further understand pathomechanisms during renal ischemia in rodents and identify treatable targets to ultimately correlate them in human biosamples. If successful, those findings could improve organ graft function and patient outcome.
DFG Programme
WBP Fellowship
International Connection
USA
