European Commission logo
English English
CORDIS - EU research results
CORDIS

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

Project description

A novel approach for treating malaria

Ferroptosis is a newly discovered process of iron-dependent cell death that seems to be implicated in various diseases including malaria. Scientists of the EU-funded RIGM project are working under the hypothesis that the modulation of iron metabolism could serve as a novel therapeutic intervention against malaria. Research efforts will focus on the investigation of ferroptosis in the kidneys during malaria and its impact on glucose metabolism. Transcriptomic and metabolomic analyses in a mouse model of the disease are expected to unveil novel targets of ferroptosis manipulation and help scientists understand how iron metabolism affects organ homeostasis.

Objective

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.

Coordinator

FUNDACAO CALOUSTE GULBENKIAN
Net EU contribution
€ 147 815,04
Address
AVENIDA BERNA 45A
1067-001 LISBOA
Portugal

See on map

Region
Continente Área Metropolitana de Lisboa Área Metropolitana de Lisboa
Activity type
Research Organisations
Links
Total cost
€ 147 815,04