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

Opis projektu

Nowe podejście do leczenia malarii

Ferroptoza jest nowo odkrytym procesem zależnej od żelaza śmierci komórek, który wydaje się być powiązany z różnymi chorobami, w tym malarią. Naukowcy skupieni wokół finansowanego przez UE projektu RIGM badają hipotezę, zgodnie z którą modulacja metabolizmu żelaza może zostać wykorzystana jako nowa interwencja terapeutyczna przeciwko malarii. Wysiłki badawcze skoncentrują się na badaniu ferroptozy w nerkach w czasie malarii oraz jej wpływu na metabolizm glukozy. Analizy transkryptomiczne i metabolomiczne w modelu mysim pozwolą wyłonić nowe cele manipulacji ferroptozą oraz pomogą naukowcom zrozumieć, jak metabolizm żelaza wpływa na homeostazę narządów.

Cel

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.