RIGM · Renal iron homeostasis tackles with glucose metabolism to confer disease tolerance in malaria infection
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2020-06-01 → 2022-05-31
- Финансиране от ЕС
- 147 815 €
- Участници
- 1
- Схема
- MSCA-IF-EF-ST
Линиите свързват координатора с партньорите.
Накратко на български
Ролята на протеина SLC40A1 при извеждането на желязо от бъбреците се анализира чрез миша модели, за да се види как това влияе върху метаболизма на глюкозата при малария. Това помага за разбирането на механизмите за устойчивост на организма и търсенето на нови терапевтични цели.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Renal iron homeostasis tackles with glucose metabolism to confer disease tolerance in malaria infection
Malaria is a top rank infectious disease worldwide caused by Plasmodium infection. In RIGM, we proposed that the sole iron exporter ferroportin (encoded by Solute Carrier Family 40 Member 1, Slc40a1) promotes disease tolerance to malaria via renal iron control. We aimed to unravel potential crosstalk with renal ferroptosis cascade and glucose metabolism, dictated by SLC40A1. Malaria is a heavy burden in developing countries. Together with other tropical infectious diseases, they are threatening the non-endemic regions due to climate change. RIGM sought to obtain knowledge directly related to the role of Slc40a1 in the establishment of disease tolerance in malaria. It should generate fundamental academic knowledge and provide potential therapeutic targets. The main objective of RIGM was to identify and characterize the role of renal iron export by Slc40a1 in establishing disease tolerance to malaria, by using a combination of conditional/inducible gene deletion mouse models and Plasmodium infection model, to test iron export controls for the development of ferroptotic tissue damage and kidney gluconeogenesis during malaria.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
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.
Оригинален текст от CORDIS (на английски).
Участници
- FUNDACAO CALOUSTE GULBENKIAN · LisboaКоординаторПортугалия
Връзки
Данни: CORDIS, © Европейски съюз