Hereditary hemochromatosis (HH) is the most common inherited disorder in people of Northern European descent. Iron overload damages organs leading to cirrhosis of the liver, diabetes, cardiomyopathy, and arthritis. Transferrin receptor 2 (TfR2) is a recently described protein with sequence similarity to the ubiquitous transferrin receptor (TfRl). The function of TfR2 is unknown. Mutated forms of TfR2 cause a form of hereditary hemochromatosis thus, implicating TfR2 as a key protein in the regulation of iron homeostasis in the body. TfR2 is found almost exclusively in hepatocytes. The liver is the major iron processing organ in the body, and iron sensing by this organ affects iron absorption by the intestines. Recent evidence shows that physiological concentrations of diferric transferrin (Tf) regulate TfR2 levels in hepatoma cell lines. Mouse models of iron overload support these findings. Since concentrations of diferric Tf generally reflect body iron levels in nonpathological conditions, TfR2 could signal iron levels by sensing diferric Tf. A model of how TfR2 senses Tf saturation and responds to regulate iron homeostasis in the body will be tested. The long term goal of this research is to understand how mutations in key proteins disturb the iron balance in the body and thereby reveal the mechanisms by which the body regulates iron homeostasis.