Modulation of the cGAS-STING signaling pathway and mitochondrial protection by AP39 and normothermic machine perfusion in ischemia-induced kidney damage prior kidney transplantation

• Applicant: Dr. Clara Antonia Weigle
• Subject Area: General and Visceral Surgery
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 582692315

The proposed project investigates novel strategies to improve the quality of kidney graft by targeted modulation of mitochondrial protective mechanisms and subsequent inflammatory process. Particularly in kidneys from so-called extended criteria donors (ECD) or donors after circulatory death (DCD) – which are increasingly used due to the mismatch between available and required donor organs – ischemia-reperfusion injury (IRI) leads to mitochondrial dysfunction, oxidative stress, and activation of the cGAS-STING signaling pathway. These processes result in acute tissue damage, inflammation, and long-term fibrotic remodeling, thereby severely impairing graft function and consequently the quality of life and life expectancy of transplant recipients. The aim of this project is to characterize the protective mechanisms of normothermic ex-vivo kidney perfusion (NEVKP) in combination with the mitochondria-targeted H2S donor AP39. Previous studies from the host institution (Selzner Lab, Toronto) demonstrated that these synergistic preconditioning strategies preserve mitochondrial integrity, reduce oxidative stress, and significantly improve the function of marginal donor kidneys. Building on these finding, we will systematically investigate the underlying cellular and molecular mechanisms. Work packages: 1. In-vivo analysis of mitochondrial morphology and function in different renal cell types after IRI under NEVKP±AP39 using transcriptomic, histology, and functional assays. 2. In-vitro investigation of how AP39 protects individual cell types (tubular, endothelial, and immune cells) from IRI, including analyses of oxidative stress, mitophagy, regulated cell death, and involvement of specific signaling pathways (cGAS-STING and NFϰB). 3. Validation and optimization in a preclinical large-animal model with prolonged warm ischemia (120 min) to assess therapeutic efficacy and prepare for clinical pilot study. This project combines cutting-edge experimental transplantation research with strong clinical relevance and aims to develop new therapeutic strategies to reduce IRI, prevent graft fibrosis, and prolong organ survival.

• DFG Programme: Fellowship
• International Connection: Canada
• Host: Professor Dr. Markus Selzner