Scientific area
3.1 Basic medicine
Discipline(s)
Pharmacology and pharmacy
Project title
A role for Nrf2/ARE cytoprotective signalling in iron overload. Adaptive response to oxidative stress as a disease modifier in HFE associated hereditary hemochromatosis
Scientific Coordinator's name:
Tiago Duarte
Scientific Coordinator's e-mail:
tduarte@ibmc.up.pt
Principal R&D Unit:
Iron and Innate Immunity
Other R&D Units involved in the project:
Other R&D units involved in the project
Project keyword(s)
iron, hemochromatosis, antioxidant, oxidative stress, Nrf2
Short abstract and comments
HFE-associated hereditary hemochromatosis (HH) is the most common genetic disorder of iron overload among Caucasians. If untreated, it can lead to total body iron overload with secondary tissue damage in several organs attributed to oxidative stress. Most HH patients are homozygous for the C282Y mutation in the HFE gene, but symptoms are highly variable. It remains elusive why some patients exhibit a clinically severe disease while most C282Y homozygotes are apparently healthy. We hypothesize that resistance to oxidative stress may be a modifier of disease progression in HFE-HH and other iron overload-related pathologies. Systemic adaptation to oxidative stress is associated with the induction of a set of genes encoding proteins with antioxidative and cytoprotective functions. Transcription factor Nrf2 regulates transcriptional induction of such genes and there is growing evidence that Nrf2 is an important modifier of diseases involving oxidative stress. Moreover, polymorphisms in the Nrf2 pathway may compromise the adaptive antioxidant response. This project aims at: a) understanding the protective role of Nrf2 in iron overload disease; and b) testing the hypothesis that resistance to oxidative stress may be a modifier of disease progression in HFE-HH. We will address these issues using a combination of cellular and animal models of iron overload, as well as blood cells from human HH patients.
Potential uses/indications
It is expected that this study will elucidate the protective role of Nrf2 in iron overload disease and provide important new information that will help determine which C282Y homozygotes are at increased risk to develop iron overload-related tissue damage.
Status
Ongoing
Partner Status: Seeking Partners?
No
Grant number (QREN, FP7, Eureka, etc)
PTDC/SAU-FCF/101177/2008
Last edited on
2013-01-30 17:17:47