Renal iron homeostasis tackles with glucose metabolism to confer disease tolerance in malaria infection

Description du projet

Une approche innovante pour traiter le paludisme

La ferroptose est un processus de mort cellulaire dépendante du fer qui vient d’être découvert et qui semble être impliqué dans plusieurs maladies, dont le paludisme. Les scientifiques du projet RIGM, financé par l’UE, travaillent en partant de l’hypothèse que la modulation du métabolisme du fer pourrait constituer une nouvelle intervention thérapeutique contre le paludisme. Les efforts de recherche se concentreront sur l’étude de la ferroptose dans les reins dans le cadre du paludisme et ses répercussions sur le métabolisme du glucose. Des analyses métabolomiques et transcriptomiques sur un modèle murin de la maladie devraient dévoiler de nouvelles cibles de manipulation de la ferroptose et permettre aux scientifiques de comprendre la manière dont le métabolisme du fer influence l’homéostasie des organes.

Objectif

Disease tolerance is pivotal for host survival in malaria. In particular, Heme/iron metabolism in parenchymal tissues, such as liver, kidney, implicates in tissue damage and metabolic reprogram during infection diseases including malaria and sepsis, etc. Therefore, heme/iron metabolism is potential target for disease tolerance modulation in treating malaria and sepsis. In support of this notion, the host lab previously found that Ho-1 and ferritin heavy chain in the kidney are important in mice fighting against malaria. Meanwhile, the underlying mechanism of heme/iron affecting organ metabolism and host homeostasis is not well understood. Studies indicated that ferroptosis cascade involves in heme/iron-driven tissue damage and other metabolic alterations. Accordingly, we intend to address the interface of ferroptosis and glucose metabolism in kidney during malaria. Malaria iwill be applied to iron exporter, Ferroportin (Slc40a1) deletion specific in renal proximal tubule epithelial cells(RPTEC) (Slc40a1 PepckΔ/Δ ). Basic disease trajectory phenotype and ferroptosis parameters will be collected to demonstrate the impact of RPTEC iron export on kidney injury and systematic homeostatic status during malaria. Based on our preliminary data, Slc40a1 PepckΔ/Δ mice are sensitive to malaria due to disease tolerance collapse which displays as lethal hypoglycaemia and temperature drop. We propose to manipulate ferroptosis cascade to ameliorate tissue damage and re-establish disease tolerance in Slc40a1 PepckΔ/Δ mice. Furthermore, we aim to investigate to interface between ferroptosis cascade and glucose metabolism. Not only will a pivotal role of renal glucose production fine-tuned by heme/iron metabolism be uncovered. Transcriptome and metabolomics will be employed to identify novel pathway/metabolites that tackle both ferroptosis and glucose metabolism. The future potency of this study, is to provide therapeutic target in treating malaria.