Iron homeostasis is tightly regulated to provide this critical element for growth and survival, but to prevent the toxicity of iron excess. Abnormal regulation of systemic iron balance leads to common diseases including anemia and the iron overload disorder hereditary hemochromatosis. Hepcidin is a master regulator of overall body iron balance that acts by downregulating the cell-surface expression of the iron exporter ferroportin to control iron absorption from the diet and iron release from body stores. However, the mechanisms by which iron levels are sensed by the liver to regulate hepcidin expression are not fully understood. We have previously demonstrated that 1) hemojuvelin (HJV) is a co-receptor for the bone morphogenetic protein (BMP)-SMAD signaling pathway, which is a central transcriptional regulator of hepcidin expression in the liver, 2) BMP6 is a key endogenous ligand of HJV in the regulation of hepcidin expression and systemic iron balance, 3) the BMP-SMAD signaling pathway is critical to hepcidin regulation by iron, 4) there are at least two mechanisms by which iron activates the BMP-SMAD pathway: liver iron induces liver BMP6 mRNA expression and circulating iron stimulates SMAD signaling downstream of BMP6, 5) the BMP- SMAD signaling pathway intersects with most other known hepcidin regulatory pathways including the hemochromatosis proteins HFE and TFR2 and inflammation, and 6) modulators of the BMP-SMAD pathway regulate hepcidin expression to treat hemochromatosis and anemia of chronic disease in animal models. These studies have already yielded important insights into the pathophysiology of hemochromatosis and have identified the BMP-SMAD pathway as a novel therapeutic target for iron disorders. In this competing renewal, we will address important unanswered questions about how iron is sensed by the liver to regulate hepcidin, and the key role of the BMP-SMAD pathway in this process.
In Specific Aim I, we will use our novel conditional Bmp6 KO mice in specific liver cell populations to determine the cellular source of BMP6 that regulates hepcidin expression, and we will use in vitro approaches together with an in vivo bioluminescence assay in mice to elucidate the molecular mechanisms underlying iron-mediated BMP6 induction.
In Specific Aim II, we will use genetic and pharmacologic approaches in vivo coupled with biochemical and cell culture studies to identify other specific functional components of the BMP-SMAD signaling cascade that are critical for hepcidin regulation and iron homeostasis. The long-term goals of this project are to understand the role of the BMP signaling pathway in regulating hepcidin expression and systemic iron balance, to gain insights into the physiology and pathophysiology of iron homeostasis in health and disease, and ultimately to develop new therapeutic strategies for treating disorders of iron metabolism.
Diseases related to iron deficiency or iron overload are a significant public health problem affecting nearly 1 billion people worldwide. This proposal will investigate a novel regulatory pathway that plays a key role in maintaining iron balance in the body. Our goal is to understand how iron balance is controlled, and to discover new ways to treat iron disorders such as anemia, thalassemia, and hemochromatosis.
|Canali, Susanna; Wang, Chia-Yu; Zumbrennen-Bullough, Kimberly B et al. (2017) Bone morphogenetic protein 2 controls iron homeostasis in mice independent of Bmp6. Am J Hematol 92:1204-1213|
|Wang, Chia-Yu; Core, Amanda B; Canali, Susanna et al. (2017) Smad1/5 is required for erythropoietin-mediated suppression of hepcidin in mice. Blood 130:73-83|
|Dev, Som; Babitt, Jodie L (2017) Overview of iron metabolism in health and disease. Hemodial Int 21 Suppl 1:S6-S20|
|David, Valentin; Francis, Connor; Babitt, Jodie L (2017) Ironing out the cross talk between FGF23 and inflammation. Am J Physiol Renal Physiol 312:F1-F8|
|Canali, Susanna; Zumbrennen-Bullough, Kimberly B; Core, Amanda B et al. (2017) Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice. Blood 129:405-414|
|He, Qing; Bouley, Richard; Liu, Zun et al. (2017) Large G protein ?-subunit XL?s limits clathrin-mediated endocytosis and regulates tissue iron levels in vivo. Proc Natl Acad Sci U S A 114:E9559-E9568|
|David, Valentin; Martin, Aline; Isakova, Tamara et al. (2016) Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int 89:135-46|
|Theurl, Igor; Hilgendorf, Ingo; Nairz, Manfred et al. (2016) On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver. Nat Med 22:945-51|
|Canali, Susanna; Core, Amanda B; Zumbrennen-Bullough, Kimberly B et al. (2016) Activin B Induces Noncanonical SMAD1/5/8 Signaling via BMP Type I Receptors in Hepatocytes: Evidence for a Role in Hepcidin Induction by Inflammation in Male Mice. Endocrinology 157:1146-62|
|Canali, Susanna; Vecchi, Chiara; Garuti, Cinzia et al. (2016) The SMAD Pathway Is Required for Hepcidin Response During Endoplasmic Reticulum Stress. Endocrinology 157:3935-3945|
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