Babitt, Jodie, MD

Associate Professor

Phone: 617-726-0429
Email: Babitt.Jodie@mgh.harvard.edu
Lab: Babitt, Jodie
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 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 recently discovered that the bone morphogenetic protein (BMP) 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, and this is thought be one mechanism underlying the anemia of chronic disease. In contrast, hepcidin deficiency, which causes excessive dietary iron absorption and progressive tissue iron deposition and dysfunction, appears to be the common pathogenic mechanism underlying the iron overload disorder hereditary hemochromatosis. Our lab has recently shown that 1) mutations in either the BMP co-receptor hemojuvelin or BMP6 ligand each lead to hepcidin deficiency and severe hemochromatosis; 2) iron regulates BMP ligand expression and BMP signal transduction in the liver; and 3) modulation of the BMP 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.

Publications

  • Xiao X, Dev S, Canali S, Bayer A, Xu Y, Agarwal A, Wang CY, Babitt JL Endothelial Bmp2 knockout exacerbates hemochromatosis in Hfe knockout mice but not Bmp6 knockout mice. Hepatology. 2019;:ePub - PMID: 31778583 - DOI: 10.1002/hep.31048

  • Lim PJ, Duarte TL, Arezes J, Garcia-Santos D, Hamdi A, Pasricha SR, Armitage AE, Mehta H, Wideman S, Santos AG, Santos-Gonçalves A, Morovat A, Hughes JR, Soilleux E, Wang CY, Bayer AL, Klenerman P, Willberg CB, Hartley RC, Murphy MP, Babitt JL, Ponka P, Porto G, Drakesmith H Nrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin. Nat Metab. 2019;1(5):519-531 - PMID: 31276102 - PMCID: PMC6609153 - DOI: 10.1038/s42255-019-0063-6

  • Babitt JL Ironing out pulmonary arterial hypertension. Proc Natl Acad Sci U S A. 2019;116(26):12604-12606 - PMID: 31171658 - PMCID: PMC6601273 - DOI: 10.1073/pnas.1908298116

  • Babitt JL, Sitara D Crosstalk between fibroblast growth factor 23, iron, erythropoietin, and inflammation in kidney disease. Curr Opin Nephrol Hypertens. 2019;28(4):304-310 - PMID: 31145704 - PMCID: PMC6693648 - DOI: 10.1097/MNH.0000000000000514

  • Wang CY, Xiao X, Bayer A, Xu Y, Dev S, Canali S, Nair AV, Masia R, Babitt JL Ablation of hepatocyte Smad1, Smad5 and Smad8 causes severe tissue iron loading and liver fibrosis in mice. Hepatology. 2019;70(6):1986-2002 - PMID: 31127639 - PMCID: PMC6874904 - DOI: 10.1002/hep.30780

  • Leaf DE, Rajapurkar M, Lele SS, Mukhopadhyay B, Boerger EAS, Mc Causland FR, Eisenga MF, Singh K, Babitt JL, Kellum JA, Palevsky PM, Christov M, Waikar SS Iron, Hepcidin, and Death in Human AKI. J Am Soc Nephrol. 2019;30(3):493-504 - PMID: 30737269 - PMCID: PMC6405140 - DOI: 10.1681/ASN.2018100979

  • He Q, Bouley R, Liu Z, Wein MN, Zhu Y, Spatz JM, Wang CY, Divieti Pajevic P, Plagge A, Babitt JL, Bastepe M Large G protein α-subunit XLαs limits clathrin-mediated endocytosis and regulates tissue iron levels in vivo. Proc Natl Acad Sci U S A. 2017;114(45):E9559-E9568 - PMID: 29078380 - PMCID: PMC5692581 - DOI: 10.1073/pnas.1712670114

  • Canali S, Wang CY, Zumbrennen-Bullough KB, Bayer A, Babitt JL Bmp2 controls iron homeostasis in mice independent of Bmp6. Am J Hematol. 2017;92(11):1204-1213 - PMID: 28815688 - PMCID: PMC5986189 - DOI: 10.1002/ajh.24888

  • Wang CY, Core AB, Canali S, Zumbrennen-Bullough KB, Ozer S, Umans L, Zwijsen A, Babitt JL Smad1/5 is required for erythropoietin-mediated suppression of hepcidin in mice. Blood. 2017;130(1):73-83 - PMID: 28438754 - PMCID: PMC5501149 - DOI: 10.1182/blood-2016-12-759423

  • Dev S, Babitt JL Overview of iron metabolism in health and disease. Hemodial Int. 2017;21 Suppl 1:S6-S20 - PMID: 28296010 - PMCID: PMC5977983 - DOI: 10.1111/hdi.12542

  • Sise ME, Wisocky J, Rosales IA, Chute D, Holmes JA, Corapi KM, Babitt JL, Tangren JS, Hashemi N, Lundquist AL, Williams WW, Mount DB, Andersson KL, Rennke HG, Smith RN, Colvin R, Thadhani RI, Chung RT Lupus-like Immune Complex-mediated Glomerulonephritis in Patients with Hepatitis C Virus Infection Treated with Oral, Interferon-free, Direct-acting Antiviral Therapy. Kidney Int. 2016;1(3):135-143 - PMID: 27990496 - PMCID: PMC5155703 - DOI: 10.1016/j.ekir.2016.06.006

  • Canali S, Vecchi C, Garuti C, Montosi G, Babitt JL, Pietrangelo A The SMAD pathway is required for hepcidin response during endoplasmic reticulum stress. Endocrinology. 2016;:en20161258 - PMID: 27483343 - PMCID: PMC5045507 - DOI: 10.1210/en.2016-1258

  • Theurl I, Hilgendorf I, Nairz M, Tymoszuk P, Haschka D, Asshoff M, He S, Gerhardt LM, Holderried TA, Seifert M, Sopper S, Fenn AM, Anzai A, Rattik S, McAlpine C, Theurl M, Wieghofer P, Iwamoto Y, Weber GF, Harder NK, Chousterman BG, Arvedson TL, McKee M, Wang F, Lutz OM, Rezoagli E, Babitt JL, Berra L, Prinz M, Nahrendorf M, Weiss G, Weissleder R, Lin HY, Swirski FK On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver. Nature Med. 2016;22(8):945-951 - PMID: 27428900 - PMCID: PMC4957133 - DOI: 10.1038/nm.4146

  • Wang CY, Babitt JL Hepcidin regulation in the anemia of inflammation. Curr Opin Hematol. 2016;23(3):189-197 - PMID: 26886082 - PMCID: PMC4993159 - DOI: 10.1097/MOH.0000000000000236

  • 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 - PMID: 26735394 - PMCID: PMC4769363 - DOI: 10.1210/en.2015-1747

  • Samir AE, Allegretti AS, Zhu Q, Dhyani M, Anvari A, Sullivan DA, Trottier CA, Dougherty S, Williams WW, Babitt JL, Wenger J, Thadhani RI, Lin HY Shear wave elastography in chronic kidney disease: a pilot experience in native kidneys. BMC Nephrol. 2015;16(1):119 - PMID: 26227484 - PMCID: PMC4521488 - DOI: 10.1186/s12882-015-0120-7

  • Tesfay L, Clausen KA, Kim JW, Hedge P, Wang X, Miller LD, Deng Z, Blanchette N, Arvedson T, Miranti CK, Babitt JL, Lin HY, Peehl DM, Torti FM, Torti SV Hepcidin regulation in prostate and its disruption in prostate cancer. Cancer Res. 2015;75(11):2254-63 - PMID: 25858146 - PMCID: PMC4454355 - DOI: 10.1158/0008-5472.CAN-14-2465

  • Zumbrennen-Bullough K, Wu Q, Core AB, Canali S, Chen W, Theurl I, Meynard D, Babitt JL MicroRNA-130a is upregulated 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 - PMID: 25002578 - PMCID: PMC4156078 - DOI: 10.1074/jbc.M114.577387

  • Core AB, Canali S, Babitt JL Hemojuvelin and bone morphogenetic protein (BMP) signaling in iron homeostasis. Front Pharmacol. 2014;5:104 - PMID: 24860505 - PMCID: PMC4026703 - DOI: 10.3389/fphar.2014.00104

  • Babitt JL, Lin HY BuMPing iron with modified heparins. Blood. 2014;123(10):1440-1 - PMID: 24627550 - PMCID: PMC3945857 - DOI: 10.1182/blood-2014-01-549519

  • Meynard D, Sun CC, Wu Q, Chen W, Chen S, Nelson CN, Waters MJ, Babitt JL, Lin HY Inflammation Regulates TMPRSS6 Expression via STAT5. PLoS ONE. 2013;8(12):e82127 - PMID: 24376517 - PMCID: PMC3871639 - DOI: 10.1371/journal.pone.0082127

  • 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):1733-1743 - PMID: 23345622 - PMCID: PMC3707526 - DOI: 10.1093/ndt/gfs584

  • Wu X, Yung LM, Cheng WH, Yu PB, Babitt JL, Lin HY, Xia Y Hepcidin Regulation by BMP Signaling in Macrophages Is Lipopolysaccharide Dependent. PLoS ONE. 2012;7(9):e44622 - PMID: 23028567 - PMCID: PMC3441567 - DOI: 10.1371/journal.pone.0044622

  • 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 - PMID: 23029472 - PMCID: PMC3459908 - DOI: 10.1371/journal.pone.0046307

  • Gutiérrez OM, Sun CC, Chen W, Babitt JL, Lin HY Statement of Concern about a Commercial Assay Used to Measure Soluble Hemojuvelin in Humans. Am J Nephrol. 2012;36(4):332-333 - PMID: 23006450 - DOI: 10.1159/000342519

  • Babitt JL, Lin HY Mechanisms of Anemia in CKD. J Am Soc Nephrol. 2012;23(10):1631-4 - PMID: 22935483 - PMCID: PMC3458456 - DOI: 10.1681/ASN.2011111078

  • Babitt JL, Lin HY The molecular pathogenesis of hereditary hemochromatosis. Semin Liver Dis. 2011;31(3):280-92 - PMID: 21901658 - DOI: 10.1055/s-0031-1286059

  • Corradini E, Rozier M, Meynard D, Odhiambo A, Lin HY, Feng Q, Migas MC, Britton RS, Babitt JL, Fleming RE Iron regulation of hepcidin despite attenuated Smad1,5,8 signaling in mice without transferrin receptor 2 or Hfe. Gastroenterology. 2011;141(5):1907-14 - PMID: 21745449 - PMCID: PMC3634343 - DOI: 10.1053/j.gastro.2011.06.077

  • Theurl I, Schroll A, Sonnweber T, Nairz M, Theurl M, Willenbacher W, Eller K, Wolf D, Seifert M, Sun CC, Babitt JL, Hong CC, Menhall T, Gearing P, Lin HY, Weiss G Pharmacologic inhibition of hepcidin expression reverses anemia of chronic disease in rats. Blood. 2011;118(18):4977-84 - PMID: 21730356 - PMCID: PMC3208302 - DOI: 10.1182/blood-2011-03-345066

  • Meynard D, Vaja V, Sun CC, Corradini E, Chen S, Lopez-Otin C, Grgurevic L, Hong CC, Stirnberg M, Gutschow M, Vukicevic S, Babitt JL, Lin HY Regulation of TMPRSS6 by BMP6 and iron in human cells and mice. Blood. 2011;118(3):747-56 - PMID: 21622652 - PMCID: PMC3142910 - DOI: 10.1182/blood-2011-04-348698

  • 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 - PMID: 21488083 - PMCID: PMC3277401 - DOI: 10.1002/hep.24359

  • Gibert Y, Lattanzi VJ, Zhen AW, Vedder L, Brunet F, Faasse SA, Babitt JL, Lin HY, Hammerschmidt M, Fraenkel PG BMP Signaling Modulates Hepcidin Expression in Zebrafish Embryos Independent of Hemojuvelin. PLoS ONE. 2011;6(1):e14553 - PMID: 21283739 - PMCID: PMC3024971 - DOI: 10.1371/journal.pone.0014553

  • Bolondi G, Garuti C, Corradini E, Zoller H, Vogel W, Finkenstedt A, Babitt JL, Lin HY, Pietrangelo A Altered hepatic BMP signaling pathway in human HFE hemochromatosis. Blood Cells Mol Dis. 2010;45(4):308-12 - PMID: 20863724 - PMCID: PMC3295241 - DOI: 10.1016/j.bcmd.2010.08.010

  • 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 - PMID: 20682319 - PMCID: PMC3295242 - DOI: 10.1053/j.gastro.2010.07.044

  • Babitt JL, Lin HY Molecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD. Am J Kidney Dis. 2010;55(4):726-41 - PMID: 20189278 - PMCID: PMC2905036 - DOI: 10.1053/j.ajkd.2009.12.030

  • Xia Y, Babitt JL, Bouley R, Zhang Y, Silva ND, Chen S, Zhuang Z, Samad TA, Brenner GJ, Anderson JL, Hong CC, Schneyer AL, Brown D, Lin HY Dragon Enhances BMP Signaling and Increases Transepithelial Resistance in Kidney Epithelial Cells. J Am Soc Nephrol. 2010;21(4):666-77 - PMID: 20167703 - PMCID: PMC2844302 - DOI: 10.1681/ASN.2009050511

  • Corradini E, Babitt JL, Lin HY The RGM/DRAGON family of BMP co-receptors. Cytokine Growth Factor Rev. 2009;20(5-6):389-98 - PMID: 19897400 - PMCID: PMC3715994 - DOI: 10.1016/j.cytogfr.2009.10.008

  • Wang L, Harrington L, Trebicka E, Shi HN, Kagan JC, Hong CC, Lin HY, Babitt JL, Cherayil BJ Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice. J Clin Invest. 2009;119(11):3322-8 - PMID: 19809161 - PMCID: PMC2769199 - DOI: 10.1172/JCI39939

  • Corradini E, Garuti C, Montosi G, Ventura P, Andriopoulos B, Lin HY, Pietrangelo A, Babitt JL Bone morphogenetic protein signaling is impaired in an Hfe knockout mouse model of hemochromatosis. Gastroenterology. 2009;137(4):1489-97 - PMID: 19591830 - PMCID: PMC2757523 - DOI: 10.1053/j.gastro.2009.06.057

  • Andriopoulos Jr B, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, Knutson MD, Pietrangelo A, Vukicevic S, Lin HY, Babitt JL BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 2009;41(4):482-7 - PMID: 19252486 - PMCID: PMC2810136 - DOI: 10.1038/ng.335

  • Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, Lin HY Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38(5):531-9 - PMID: 16604073 - DOI: 10.1038/ng1777

  • Babitt J, Zhang Y, Samad T, Xia Y, Tang J, Campagna J, Schneyer A, Woolf C, Lin HY Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor. J Biol Chem. 2005;280(33):29820-7 - PMID: 15975920 - DOI: 10.1074/jbc.M503511200

  • del Re E, Babitt J, Pirani A, Schneyer A, Lin HY In the absence of type III receptor, the transforming growth factor (TGF)-beta type II-B receptor requires the type I receptor to bind TGF-beta2. J Biol Chem. 2004;279(21):22765-72 - PMID: 14996829 - DOI: 10.1074/jbc.M401350200