The applicant proposes a program to prepare for a career in academic medicine and basic science research in the field of TGF-beta superfamily signaling and iron metabolism. Research will be conducted in the laboratory of Dr. Dennis Brown at MGH. Iron homeostasis is tightly regulated to provide this critical element for growth and survival, but to prevent the toxicity of iron excess. Hemojuvelin (HJV), was recently identified as the gene mutated in most cases of juvenile hemochromatosis, a severe disorder of iron overload. Although the function of HJV is unknown, hepcidin levels are depressed in persons with HJV mutations, suggesting that HJV positively regulates hepcidin expression. A soluble protein secreted by the liver, hepcidin is a critical regulator of systemic iron homeostasis whose levels are inversely correlated with iron uptake from the intestine and release from macrophages and hepatocytes. Preliminary data is presented that 1) HJV, a member of the repulsive guidance molecule (RGM) family, is a co-receptor that enhances bone morphogenetic protein (BMP) signaling;2) mutations in HJV which cause iron overload impair its BMP signaling ability;3) BMP-2 upregulates hepcidin expression;4) BMP-2 induction of hepcidin expression is blunted in Hjv-/- hepatocytes. These data reveal a novel link between the BMP signaling pathway and iron metabolism and suggest a mechanism by which HJV mutations cause hemochromatosis: HJV dysfunction decreases BMP-2 signaling, thereby lowering hepcidin expression. This proposal aims to: 1) Characterize the molecular mechanisms by which BMP-2 regulates hepcidin expression, including the interaction between this pathway and other known modulators of hepcidin expression such as inflammatory mediators, HFE, TfR2, iron overload, and anemia;2) Determine the effects of BMP-2 signaling via HJV in vivo on hepcidin expression, ferroportin expression, serum iron, and tissue iron levels;3) Determine the role of other TGF- beta superfamily members on hepcidin expression and iron metabolism. Relevance: Disorders of iron balance represent a significant public health problem affecting over a billion people worldwide. This proposal aims to investigate a novel regulatory pathway, which appears to play a key role in iron balance. It is hoped that this work will provide clues leading to new treatment strategies for disorders of iron overload such as hemochromatosis and disorders of iron deficiency such as anemia of chronic disease.
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