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A role for Nrf2/ARE cytoprotective signalling in iron overload. Adaptive response to oxidative stress as a disease modifier in HFE associated hereditary hemochromatosis

IBMC - Institute for Molecular and Cell Biology
Project classification

Scientific area

3.1 Basic medicine

Discipline(s)

Pharmacology and pharmacy

Project description

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

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