Hereditary Hemochromatosis (HH) is the most common potentially fatal inherited disorder in people of Northern European origin. Approximately 85% of the cases result from a single base-pair mutation, which converts Cys to Tyr in the HFE protein. This mutation causes a recessive disease resulting in increased iron absorption and accumulation of iron in selected tissues. The iron overload damages these organs leading to cirrhosis of the liver, diabetes, cardiomyopathy, and arthritis. Eighteen years after the cloning and identification of HFE, the mechanisms by which HFE affect iron-homeostasis remain to be determined. We hypothesize that HFE has at least two functions. It lowers iron uptake into the body, globally, by increasing the transcription of hepcidin, a hormone that negatively regulates iron efflux out of intestinal epithelial cells into the blood. HFE also negatively regulates the iron levels in the cell, locally.
Specific Aim 1 will determine the mechanism(s) by which transferrin mediates the HFE-dependent regulation of hepcidin. Several models of how HFE increases hepcidin transcription will be tested in primary hepatocyte culture, and mice.
Specific Aim 2 will determine the mechanism(s) by which HFE regulates the transport of iron into cells. The long-term goal of this work is to understand the function of HFE.

Public Health Relevance

Hereditary hemochromatosis (HH) is the most common potentially lethal inherited disease in people of N. European extraction. A single mutation in the HH protein, HFE, is responsible for 85% of cases of HH. Excess iron in tissues results in cirrhosis of the liver, increased risk of liver cancer, diabetes, heart arythmias and arthritis, usually by the fifth decade of life. In this application, we seek to define the function of HFE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK054488-16
Application #
9090048
Study Section
Special Emphasis Panel (NSS)
Program Officer
Roy, Cindy
Project Start
2000-03-01
Project End
2020-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
16
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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