Department of Pharmacology

Faculty

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Charles C. Hong, M.D., Ph.D.

Associate Professor of Medicine
Associate Professor of Cell and Developmental Biology
Associate Professor of Pharmacology
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charles.c.hong@Vanderbilt.Edu
615-936-7032
Fax: 615-936-1872
Light Hall 1155A, 2215 Garland Ave.
Nashville, TN 37232

Education

Post-doc, Harvard Medical School
Fellowship - Cardiology, Massachusetts General Hospital
Residency - Internal Medicine, Yale-New Haven Hospital
M.D., Yale
Ph.D., Yale
S.B, Massachusetts Institute of Technology

Research Keywords

Chemical biology, Cardiovascular development, Drug discovery, Zebrafish, Developmental biology, Molecular medicine, Pharmacology, Stem cells, Inherited heart diseases, Regenerative Medicine, Induced pluripotent stem cells (iPSCs).

Research Description

Our research can be divided into 2 broad areas. The first area involves chemical biology of vertebrate development, which entails discovery of small molecules that selectively modulate cell signaling pathways involved in embryogenesis. Since developmental pathways represent important untapped therapeutic targets, we have an active medicinal chemistry program to develop our novel small molecules as lead compounds for future therapies. We have thus far discovered potent and highly selective chemical modifiers of bone morphogenetic protein (BMP), Wnt, Hedgehog, and lipid signaling pathways, among others. Several of our compounds are first-in-class molecules with substantial therapeutic potential in rare and common diseases, including cancers, atherosclerosis, pulmonary hypertension and heart failure. Our chemical biology exploration has led to new opportunities for innovative therapeutic programs.

In the second, we are currently testing the utility of hiPSC to study human congenital heart diseases and inherited cardiomyopathies. We are also using iPSCs as a renewable source of human cardiomyocytes to study basic fundamental cell biology and physiology of normal and diseased cardiomyocytes. Finally, we are developing human iPSC-derived cardiomyocytes as a platform for drug testing, including validation of novel cardiac inotropes.

Publications

Talati, M, West, J, Zaynagetdinov, R, Hong, CC, Han, W, Blackwell, T, Robinson, L, Blackwell, TS, Lane, K. BMP Pathway Regulation of and by Macrophages. PLoS One, 9(4), e94119, 2014

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, 28, 1733-43, 2013

Sheng, CC Hong, CC. Pluripotent Stem Cells for Modeling Human Cardiovascular Diseases. Pluripotent Stem Cells, Chap. 20, 439-457, 2013

Williams, CH Hong, CC. Making models work: library annotation through phenoclustering. Drug Discovery Today: Disease Models, 10, e5-e9, 2013

Hao, J, Ao, A, Zhou, L, Murphy, CK, Frist, AY, Keel, JJ, Thorne, CA, Kim, K, Lee, E, Hong, CC. Selective Small Molecule Targeting ??-Catenin Function Discovered by In??Vivo Chemical Genetic Screen. Cell Rep, 4, 107, 2013

Wells, QS, Becker, JR, Su, YR, Mosley, JD, Weeke, P, D'Aoust, L, Ausborn, NL, Ramirez, AH, Pfotenhauer, JP, Naftilan, AJ, Markham, L, Exil, V, Roden, DM, Hong, CC. Whole Exome Sequencing Identifies a Causal RBM20 Mutation in a Large Pedigree with Familial Dilated Cardiomyopathy. Circ Cardiovasc Genet, 6, 317-326, 2013

Engers, DW, Frist, AY, Lindsley, CW, Hong, CC, Hopkins, CR. Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of Dorsomorphin: The discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe. Bioorg Med Chem Lett, 23(11), 3248-52, 2013

Owens, P, Polikowsky, H, Pickup, MW, Gorska, AE, Jovanovic, B, Shaw, AK, Novitskiy, SV, Hong, CC, Moses, HL. Bone morphogenetic proteins stimulate mammary fibroblasts to promote mammary carcinoma cell invasion. PLoS One, 8(6), e67533, 2013

Shelton, EL, Galindo, CL, Williams, CH, Pfaltzgraff, E, Hong, CC, Bader, DM. Autotaxin signaling governs phenotypic heterogeneity in visceral and parietal mesothelia. PLoS One, 8(7), e69712, 2013

Roden, DM, Hong, CC. Stem cell-derived cardiomyocytes as a tool for studying proarrhythmia: a better canary in the coal mine. Circulation, 127(16), 1641-3, 2013

Saeed, O, Otsuka, F, Polavarapu, R, Karmali, V, Weiss, D, Davis, T, Rostad, B, Pachura, K, Adams, L, Elliott, J, Taylor, WR, Narula, J, Kolodgie, F, Virmani, R, Hong, CC*, Finn, AV* (*Co-corresponding authors). Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis. Arterioscler Thromb Vasc Biol, 32(2), 299-307, 2012

Sheng, CC, Hong, CC. Mixing of the old with the new: nanoparticle-mediated pioglitazone delivery to enhance therapeutic neovascularization. Arterioscler Thromb Vasc Biol, 32(10), 2337-8, 2012

Ao, A, Hao, J, Hopkins, CR, Hong, CC. DMH1, a Novel BMP Small Molecule Inhibitor, Increases Cardiomyocyte Progenitors and Promotes Cardiac Differentiation in Mouse Embryonic Stem Cells. PLoS One, 7(7), e41627, 2012

Wang, L, Trebicka, E, Fu, Y, Ellenbogen, S, Hong, CC, Babitt, JL, Lin, HY, Cherayil, BJ. The bone morphogenetic protein-hepcidin axis as a therapeutic target in inflammatory bowel disease. Inflamm Bowel Dis, 18(1), 112-9, 2012

Hill, CR, Sanchez, NS, Love, JD, Arrieta, JA, Hong, CC, Brown, CB, Austin, AF, Barnett, JV. BMP2 signals loss of epithelial character in epicardial cells but requires the Type III TGFI? receptor to promote invasion. Cell Signal, 24(5), 1012-22, 2012

Neely, MD, Litt, MJ, Tidball, AM, Li, GG, Aboud, AA, Hopkins, CR, Chamberlin, R, Hong, CC, Ess, KC, Bowman, AB. DMH1, a Highly Selective Small Molecule BMP Inhibitor Promotes Neurogenesis of hiPSCs: Comparison of PAX6 and SOX1 Expression during Neural Induction. ACS Chem Neurosci, 3(6), 482-91, 2012

Wiley, DM, Kim, JD, Hao, J, Hong, CC, Bautch, VL, Jin, SW. Distinct signalling pathways regulate sprouting angiogenesis from the dorsal aorta and the axial vein. Nat Cell Biol, 13(6), 686-92, 2011

Williams, CH, Hong, CC. Multi-step usage of in vivo models during rational drug design and discovery. Int J Mol Sci, 12(4), 2262-74, 2011

Hao, J, Sawyer, DB, Hatzopoulos, AK, Hong, CC. Recent Progress on Chemical Biology of Pluripotent Stem Cell Self-renewal, Reprogramming and Cardiomyogenesis. Rec Pat Regen Med, 1(3), 263-274, 2011

Wells, QS, Ausborn, NL, Funke, BH, Pfotenhauer, JP, Fredi, JL, Baxter, S, Disalvo, TD, Hong, CC. Familial dilated cardiomyopathy associated with congenital defects in the setting of a novel VCL mutation (Lys815Arg) in conjunction with a known MYPBC3 variant. Cardiogenetics, 1(1), 2011

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 inflammation in rats. Blood, 118(18), 4977-84, 2011

Ao, A, Williams, CH, Hao, J, Hong, CC. Modified mouse embryonic stem cell based assay for quantifying cardiogenic induction efficiency. J Vis Exp(50), 2011

The International Clinical Consortium on FOP (Hong, CC, contributing member) . The medical management of Fibrodysplasia Ossificans Progressiva: current management considerations. Clin Proc Intl Clin Consort FOP(3), 1-100, 2011

Shi, S, Hoogaars, WM, de Gorter, DJ, van Heiningen, SH, Lin, HY, Hong, CC, Kemaladewi, DU, Aartsma-Rus, A, ten Dijke, P, ''t Hoen, PA. BMP antagonists enhance myogenic differentiation and ameliorate the dystrophic phenotype in a DMD mouse model. Neurobiol Dis, 41(2), 353-60, 2011

Wang, H, Hao, J, Hong, CC. Cardiac induction of embryonic stem cells by a small molecule inhibitor of Wnt/I?-catenin signaling. ACS Chem Biol, 6(2), 192-7, 2011

Xia, Y, Cortez-Retamozo, V, Niederkofler, V, Salie, R, Chen, S, Samad, TA, Hong, CC, Arber, S, Vyas, JM, Weissleder, R, Pittet, MJ, Lin, HY. Dragon (repulsive guidance molecule b) inhibits IL-6 expression in macrophages. J Immunol, 186(3), 1369-76, 2011

Palmisano, BT, Rottman, JN, Wells, QS, DiSalvo, TG, Hong, CC. Familial evaluation for diagnosis of arrhythmogenic right ventricular dysplasia. Cardiology, 119(1), 47-53, 2011

Ao, A, Hao, J, Hong, CC. Regenerative chemical biology: current challenges and future potential. Chem Biol, 18(4), 413-24, 2011

Gupta, MK, Walthall, JM, Venkataraman, R, Crowder, SW, Jung, DK, Yu, SS, Feaster, TK, Wang, X, Giorgio, TD, Hong, CC, Baudenbacher, FJ, Hatzopoulos, AK, Sung, HJ. Combinatorial polymer electrospun matrices promote physiologically-relevant cardiomyogenic stem cell differentiation. PLoS One, 6(12), e28935, 2011

Meynard, D, Vaja, V, Sun, CC, Corradini, E, Chen, S, L??pez-Ot?-n, C, Grgurevic, L, Hong, CC, Stirnberg, M, G??tschow, M, Vukicevic, S, Babitt, JL, Lin, HY. Regulation of TMPRSS6 by BMP6 and iron in human cells and mice. Blood, 118(3), 747-56, 2011

Hao, J, Zhou, L, Hong, CC. Chemical biology of pluripotent stem cells: focus on cardiomyogenesis. Embryonic Stem Cells, Chap 3, 51-64, 2011

Xia, Y, Babitt, JL, Bouley, R, Zhang, Y, Da Silva, N, 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, 21(4), 666-77, 2010

Harris, B, Pfotenhauer, JP, Silverstein, CA, Markham, LW, Schafer, K, Exil, VJ, Hong, CC. Serial observations and mutational analysis of an adoptee with family history of hypertrophic cardiomyopathy. Cardiol Res Pract, 2010, 697269, 2010

Kaplan, FS, Zasloff, MA, Kitterman, JA, Shore, EM, Hong, CC, Rocke, DM. Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am, 92(3), 686-91, 2010

Alfaro, MP, Vincent, A, Saraswati, S, Thorne, CA, Hong, CC, Lee, E, Young, PP. sFRP2 suppression of bone morphogenic protein (BMP) and Wnt signaling mediates mesenchymal stem cell (MSC) self-renewal promoting engraftment and myocardial repair. J Biol Chem, 285(46), 35645-53, 2010

Hao, J, Williams, CH, Webb, ME, Hong, CC. Large scale zebrafish-based in vivo small molecule screen. J Vis Exp(46), 2010

Hao J, Daleo MA, Hong CC. Crosstalk between mitogen-activated protein kinase and phosphoinositide-3 kinase signaling pathways in development and disease. Systems Biology for Signaling Network, Ed. Choi S., Springer, New York, Ch 21, 505-529, 2010

Hao, J, Ho, JN, Lewis, JA, Karim, KA, Daniels, RN, Gentry, PR, Hopkins, CR, Lindsley, CW, Hong, CC. In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors. ACS Chem Biol, 5(2), 245-53, 2010

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, 119(11), 3322-8, 2009

Hong, CC, Yu, PB. Applications of small molecule BMP inhibitors in physiology and disease. Cytokine Growth Factor Rev, 20(5-6), 409-18, 2009

Hong, CC. Large-scale small-molecule screen using zebrafish embryos. Methods Mol Biol, 486, 43-55, 2009

Hong, CC, Kume, T, Peterson, RT. Role of crosstalk between phosphatidylinositol 3-kinase and extracellular signal-regulated kinase/mitogen-activated protein kinase pathways in artery-vein specification. Circ Res, 103(6), 573-9, 2008

The International Clinical Consortium on FOP (Hong, CC, contributing member). The medical management of Fibrodysplasia Ossificans Progressiva: current management considerations. Clin Proc Intl Clin Consort FOP, 3, 1-82, 2008

Yu, PB, Deng, DY, Lai, CS, Hong, CC, Cuny, GD, Bouxsein, ML, Hong, DW, McManus, PM, Katagiri, T, Sachidanandan, C, Kamiya, N, Fukuda, T, Mishina, Y, Peterson, RT, Bloch, KD. BMP type I receptor inhibition reduces heterotopic [corrected] ossification. Nat Med, 14(12), 1363-9, 2008

Yu, PB, Deng, DY, Beppu, H, Hong, CC, Lai, C, Hoyng, SA, Kawai, N, Bloch, KD. Bone morphogenetic protein (BMP) type II receptor is required for BMP-mediated growth arrest and differentiation in pulmonary artery smooth muscle cells. J Biol Chem, 283(7), 3877-88, 2008

Hao, J, Daleo, MA, Murphy, CK, Yu, PB, Ho, JN, Hu, J, Peterson, RT, Hatzopoulos, AK, Hong, CC. Dorsomorphin, a selective small molecule inhibitor of BMP signaling, promotes cardiomyogenesis in embryonic stem cells. PLoS ONE, 3(8), e2904, 2008

Yu, PB*, Hong, CC*, Sachidanandan, C, Babitt, JL, Deng, DY, Hoyng, SA, Lin, HY, Bloch, KD, Peterson, RT (*co-first authors). Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol, 4(1), 33-41, 2008

Hong, CC, Peterson, QP, Hong, JY, Peterson, RT. Artery/vein specification is governed by opposing phosphatidylinositol-3 kinase and MAP kinase/ERK signaling. Curr Biol, 16(13), 1366-72, 2006

LeMosy, EK, Hong, CC, Hashimoto, C. Signal transduction by a protease cascade. Trends Cell Biol, 9(3), 102-7, 1999

Hong, CC, Hashimoto, C. The maternal nudel protein of Drosophila has two distinct roles important for embryogenesis. Genetics, 143(4), 1653-61, 1996

de la Monte, SM, Quertermous, T, Hong, CC, Bloch, KD. Regional and maturation-associated expression of endothelin 2 in rat gastrointestinal tract. J Histochem Cytochem, 43(2), 203-9, 1995

Hong, CC, Hashimoto, C. An unusual mosaic protein with a protease domain, encoded by the nudel gene, is involved in defining embryonic dorsoventral polarity in Drosophila. Cell, 82(5), 785-94, 1995

Cicila, GT, Rapp, JP, Bloch, KD, Kurtz, TW, Pravenec, M, Kren, V, Hong, CC, Quertermous, T, Ng, SC. Cosegregation of the endothelin-3 locus with blood pressure and relative heart weight in inbred Dahl rats. J Hypertens, 12(6), 643-51, 1994

Bloch, KD, Hong, CC, Eddy, RL, Shows, TB, Quertermous, T. cDNA cloning and chromosomal assignment of the endothelin 2 gene: vasoactive intestinal contractor peptide is rat endothelin 2. Genomics, 10(1), 236-42, 1991