A team led by researchers from Mass General has uncovered key molecular step stones in alcohol-related liver disease that may provide targets for drug therapy development.
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About the Lab
My laboratory is focused on elucidating the molecular and cellular mechanisms involved in iron homeostasis. Our ultimate goal is to identify new treatment strategies for disorders of iron homeostasis, such as the anemia of chronic disease (including the anemia of chronic kidney disease) and the iron overload disorder hemochromatosis.
Based on its ability to donate and accept electrons, iron is essential for many biological reactions important for living organisms including oxygen transport, cellular respiration, and DNA synthesis. However, this same property makes excess iron toxic by generating free radicals that can damage lipid membranes, proteins, and nucleic acids leading to cell death. As a result, iron levels must be tightly regulated both on a cellular level and systemically.
We have discovered that the bone morphogenetic protein (BMP)-SMAD signaling pathway plays an important role in systemic iron balance by modulating expression of the main iron regulatory hormone hepcidin.
A soluble protein secreted by the liver, hepcidin works by blocking the iron channel ferroportin, preventing iron release into the bloodstream from dietary sources and from iron storage cells. Hepcidin expression is induced by inflammation, which is thought to be part of the host defense mechanism to fight infection and cancer by limiting iron availability.
However, in chronic inflammatory states, this leads to a deficiency of iron available for red blood cell production, which is a major contributing factor to the anemia of chronic disease. In contrast, hepcidin deficiency, which causes excessive dietary iron absorption and progressive tissue iron deposition and dysfunction, is the common pathogenic mechanism underlying the iron overload disorder hereditary hemochromatosis.
Our lab has shown that 1) mutations in either the BMP co-receptor hemojuvelin or the ligand BMP6 each lead to hepcidin deficiency and severe hemochromatosis; 2) iron regulates BMP6 ligand expression and SMAD signal transduction in the liver; and 3) modulation of the BMP-SMAD signaling pathway in vivo regulates hepcidin expression and systemic iron balance.
Our current focus is working to understand the molecular and cellular mechanisms by which body iron levels are sensed and how this signal is transduced to modulate hepcidin expression and maintain systemic iron balance. We are also testing BMP-hepcidin pathway modulators as new treatment strategies for anemia of chronic disease and hemochromatosis.
Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, and Lin HY.Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Genet. 2006. 38(5): 531-9.
Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, and Lin HY.Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. Clin. Invest. 2007. 117(7): 1933-9.
Andriopoulos B Jr, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, Knutson MD, Pietrangelo A, Vukicevic S, Lin HY, and Babitt JL.BMP 6 is a key endogenous regulator of hepcidin expression and iron metabolism.Nat Genet. 41(4): 482-7.
Corradini E, Garuti C, Montosi G, Ventura P, Andriopoulos B Jr, Lin HY, Pietrangelo A, and Babitt JL. Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis.2009. 137(4): 1489-97.
Corradini E, Schmidt PJ, Meynard D, Garuti C, Montosi G, Chen S, Vukicevic S, Pietrangelo A, Lin HY, Babitt JL. BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. Gastroenterology. 2010. 139(5): 1721-9.
Corradini E, Meynard D, Wu Q, Chen S, Ventura P, Pietrangelo A, Babitt JL. Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice. Hepatology. 2011. 54(1): 273-84.
Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012; 23(10): 1631-4.
Wu Q, Sun CC, Lin HY, Babitt JL. Repulsive guidance molecule (RGM) family proteins exhibit differential binding kinetics for bone morphogenetic proteins (BMPs). PLoS One. 2012. 7(9): e46307.
Sun CC, Vaja V, Chen S, Theurl I, Stepanek A, Brown DE, Cappellini MD, Weiss G, Hong CC, Lin HY, Babitt JL. A hepcidin lowering agent mobilizes iron for incorporation into red blood cells in an adenine-induced kidney disease model of anemia in rats. Nephrol Dial Transplant. 2013. 28(7): 1733-43.
Zumbrennen-Bullough KB, Wu Q, Core AB, Canali S, Chen W, Theurl I, Meynard D, Babitt JL. MicroRNA-130a is up-regulated in mouse liver by iron deficiency and targets the bone morphogenetic protein (BMP) receptor ALK2 to attenuate BMP signaling and hepcidin transcription. J Biol Chem. 2014. 289(34): 23796-808.
David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, Zumbrennen-Bullough KB, Sun CC, Lin HY, Babitt JL, Wolf M. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int. 2015. doi: 10.1038/ki.2015.290.
Canali S, Core AB, Zumbrennen-Bullough KB, Merkulova M, Wang CY, Schneyer A, Pietrangelo A, Babitt JL. 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. 2016:en20151747
Wang CY, Babitt JL. Hepcidin Regulation in the Anemia of Inflammation. Curr Opin Hematol. 2016. In Press
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About the Nephrology Division
The Division of Nephrology at Massachusetts General Hospital is a leading provider of services for patients with kidney disease, including diagnosis and management of kidney diseases and medical management of renal transplantation.