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Mark R. Frey, PhD

Title(s)Associate Professor of Pediatrics
Phone+1 323 361 5924
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    Title(s)Admissions Chair


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    My laboratory’s research program is focused on the role of ErbB receptor tyrosine kinases in intestinal homeostasis and health. In particular, we are investigating how the neuregulin receptors ErbB4 and ErbB3 help maintain intestinal epithelial barrier integrity in the face of injury and inflammation. We were the first to report a functional role for ErbB4 in the intestine, showing that it is up-regulated in response to injury and necessary for survival of colon epithelial cells in the presence of TNF. We further demonstrated that the ErbB4-specific ligand NRG4 is protective in rodent models of inflammatory bowel disease and necrotizing enterocolitis.

    While ErbB receptor activation is potentially therapeutic for intestinal inflammation, altered expression or activity in the context of colorectal cancer could make this pathway a double-edged sword. We have demonstrated that ErbB4 expression is elevated in a substantial subset of human colon tumors. Furthermore, ErbB4 overexpression can enhance mutant Ras- and Apc-driven colonocyte transformation. Interestingly, however, it is not able to drive transformation on its own, and a subset of human tumors have quite low expression. Thus, while ErbB4 is neither necessary nor sufficient to drive tumorigenesis, it can enhance the survival of transformed cells, and targeting ErbB4 in tumors that over-express it is a potential avenue for inhibiting tumor cell survival.

    Research Interests: Signal transduction, wound healing, inflammation

    Disease Models: Cell, enteroid, and in vivo models of inflammatory bowel disease, colitis-associated colon cancer, and necrotizing enterocolitis.

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    Regulation of Colon Epithelial Cell Survival by NRG4-ErbB4 Signaling
    NIH/NIDDK R01DK095004Jul 1, 2013 - May 31, 2023
    Role: Principal Investigator
    Regulation of cyclooxygenase-2 by ErbB4 in colon epithelial cells
    NIH/NIDDK R03DK090295Apr 1, 2011 - Mar 31, 2013
    Role: Principal Investigator
    The role of ErbB-4 in inflammation-induced colon carcinogenesis
    NIH/NIDDK K01DK077956Apr 1, 2007 - Mar 31, 2012
    Role: Principal Investigator

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    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
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    1. Stanford AH, Gong H, Noonan M, Lewis AN, Gong Q, Lanik WE, Hsieh JJ, Lueschow SR, Frey MR, Good M, McElroy SJ. A direct comparison of mouse and human intestinal development using epithelial gene expression patterns. Pediatr Res. 2019 Jun 26. PMID: 31242501.
      View in: PubMed
    2. Engevik KA, Hanyu H, Matthis AL, Zhang T, Frey MR, Oshima Y, Aihara E, Montrose MH. Trefoil factor 2 activation of CXCR4 requires calcium mobilization to drive epithelial repair in gastric organoids. J Physiol. 2019 May; 597(10):2673-2690. PMID: 30912855.
      View in: PubMed
    3. Danopoulos S, Thornton ME, Grubbs BH, Frey MR, Warburton D, Bellusci S, Al Alam D. Discordant roles for FGF ligands in lung branching morphogenesis between human and mouse. J Pathol. 2019 Feb; 247(2):254-265. PMID: 30357827.
      View in: PubMed
    4. Jones JC, Brindley CD, Elder NH, Myers MG, Rajala MW, Dekaney CM, McNamee EN, Frey MR, Shroyer NF, Dempsey PJ. Cellular Plasticity of Defa4Cre-Expressing Paneth Cells in Response to Notch Activation and Intestinal Injury. Cell Mol Gastroenterol Hepatol. 2019; 7(3):533-554. PMID: 30827941.
      View in: PubMed
    5. Hou X, Chang DF, Trecartin A, Barthel ER, Schlieve CR, Frey MR, Fowler KL, Grikscheit TC. Short-term and long-term human or mouse organoid units generate tissue-engineered small intestine without added signalling molecules. Exp Physiol. 2018 12; 103(12):1633-1644. PMID: 30232817.
      View in: PubMed
    6. Frey MR. Colon Cancers Get a Negative (Selection) Attitude. Cell Mol Gastroenterol Hepatol. 2018; 6(3):349. PMID: 30182045.
      View in: PubMed
    7. Golden JM, Escobar OH, Nguyen MVL, Mallicote MU, Kavarian P, Frey MR, Gayer CP. Ursodeoxycholic acid protects against intestinal barrier breakdown by promoting enterocyte migration via EGFR- and COX-2-dependent mechanisms. Am J Physiol Gastrointest Liver Physiol. 2018 Aug 01; 315(2):G259-G271. PMID: 29672156.
      View in: PubMed
    8. Murray JA, Frey MR, Oliva-Hemker M. Celiac Disease. Gastroenterology. 2018 06; 154(8):2005-2008. PMID: 29550590.
      View in: PubMed
    9. Bower DV, Lansdale N, Navarro S, Truong TV, Bower DJ, Featherstone NC, Connell MG, Al Alam D, Frey MR, Trinh LA, Fernandez GE, Warburton D, Fraser SE, Bennett D, Jesudason EC. SERCA directs cell migration and branching across species and germ layers. Biol Open. 2017 Oct 15; 6(10):1458-1471. PMID: 28821490.
      View in: PubMed
    10. Frey MR. Bacterial Encroachment in Metabolic Syndrome: Too Much Togetherness? Cell Mol Gastroenterol Hepatol. 2017 Sep; 4(2):324-325. PMID: 28840187.
      View in: PubMed
    11. Almohazey D, Lo YH, Vossler CV, Simmons AJ, Hsieh JJ, Bucar EB, Schumacher MA, Hamilton KE, Lau KS, Shroyer NF, Frey MR. The ErbB3 receptor tyrosine kinase negatively regulates Paneth cells by PI3K-dependent suppression of Atoh1. Cell Death Differ. 2017 05; 24(5):855-865. PMID: 28304405.
      View in: PubMed
    12. Schumacher MA, Hedl M, Abraham C, Bernard JK, Lozano PR, Hsieh JJ, Almohazey D, Bucar EB, Punit S, Dempsey PJ, Frey MR. ErbB4 signaling stimulates pro-inflammatory macrophage apoptosis and limits colonic inflammation. Cell Death Dis. 2017 02 23; 8(2):e2622. PMID: 28230865.
      View in: PubMed
    13. Wieck MM, Schlieve CR, Thornton ME, Fowler KL, Isani M, Grant CN, Hilton AE, Hou X, Grubbs BH, Frey MR, Grikscheit TC. Prolonged Absence of Mechanoluminal Stimulation in Human Intestine Alters the Transcriptome and Intestinal Stem Cell Niche. Cell Mol Gastroenterol Hepatol. 2017 May; 3(3):367-388.e1. PMID: 28462379.
      View in: PubMed
    14. Frey MR. Disease-Associated Microbial Communities in Healthy Relatives: A Bacteria-Filled Crystal Ball? Cell Mol Gastroenterol Hepatol. 2016 Nov; 2(6):710-711. PMID: 28174743.
      View in: PubMed
    15. Miguel JC, Maxwell AA, Hsieh JJ, Harnisch LC, Al Alam D, Polk DB, Lien CL, Watson AJ, Frey MR. Epidermal growth factor suppresses intestinal epithelial cell shedding through a MAPK-dependent pathway. J Cell Sci. 2017 01 01; 130(1):90-96. PMID: 27026527.
      View in: PubMed
    16. Frey MR. Regenerating Reputations: Are Wnt and Myc the Good Guys After All? Dig Dis Sci. 2016 Feb; 61(2):327-9. PMID: 26520110.
      View in: PubMed
    17. Fung CM, White JR, Brown AS, Gong H, Weitkamp JH, Frey MR, McElroy SJ. Intrauterine Growth Restriction Alters Mouse Intestinal Architecture during Development. PLoS One. 2016; 11(1):e0146542. PMID: 26745886.
      View in: PubMed
    18. Dossa AY, Escobar O, Golden J, Frey MR, Ford HR, Gayer CP. Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling. Am J Physiol Gastrointest Liver Physiol. 2016 Jan 15; 310(2):G81-92. PMID: 26608185.
      View in: PubMed
    19. Buckley S, Shi W, Xu W, Frey MR, Moats R, Pardo A, Selman M, Warburton D. Increased alveolar soluble annexin V promotes lung inflammation and fibrosis. Eur Respir J. 2015 Nov; 46(5):1417-29. PMID: 26160872.
      View in: PubMed
    20. Schall KA, Holoyda KA, Grant CN, Levin DE, Torres ER, Maxwell A, Pollack HA, Moats RA, Frey MR, Darehzereshki A, Al Alam D, Lien C, Grikscheit TC. Adult zebrafish intestine resection: a novel model of short bowel syndrome, adaptation, and intestinal stem cell regeneration. Am J Physiol Gastrointest Liver Physiol. 2015 Aug 01; 309(3):G135-45. PMID: 26089336.
      View in: PubMed
    21. Williams CS, Bernard JK, Demory Beckler M, Almohazey D, Washington MK, Smith JJ, Frey MR. ERBB4 is over-expressed in human colon cancer and enhances cellular transformation. Carcinogenesis. 2015 Jul; 36(7):710-8. PMID: 25916654.
      View in: PubMed
    22. Al Alam D, Danopoulos S, Schall K, Sala FG, Almohazey D, Fernandez GE, Georgia S, Frey MR, Ford HR, Grikscheit T, Bellusci S. Fibroblast growth factor 10 alters the balance between goblet and Paneth cells in the adult mouse small intestine. Am J Physiol Gastrointest Liver Physiol. 2015 Apr 15; 308(8):G678-90. PMID: 25721301.
      View in: PubMed
    23. Michail S, Lin M, Frey MR, Fanter R, Paliy O, Hilbush B, Reo NV. Altered gut microbial energy and metabolism in children with non-alcoholic fatty liver disease. FEMS Microbiol Ecol. 2015 Feb; 91(2):1-9. PMID: 25764541.
      View in: PubMed
    24. McElroy SJ, Castle SL, Bernard JK, Almohazey D, Hunter CJ, Bell BA, Al Alam D, Wang L, Ford HR, Frey MR. The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis. Am J Pathol. 2014 Oct; 184(10):2768-78. PMID: 25216938.
      View in: PubMed
    25. Brown KS, Gong H, Frey MR, Pope B, Golden M, Martin K, Obey M, McElroy SJ. Tumor necrosis factor induces developmental stage-dependent structural changes in the immature small intestine. Mediators Inflamm. 2014; 2014:852378. PMID: 25242872.
      View in: PubMed
    26. Frey MR, Brent Polk D. ErbB receptors and their growth factor ligands in pediatric intestinal inflammation. Pediatr Res. 2014 Jan; 75(1-2):127-32. PMID: 24402051.
      View in: PubMed
    27. Williams JM, Duckworth CA, Watson AJ, Frey MR, Miguel JC, Burkitt MD, Sutton R, Hughes KR, Hall LJ, Caamaño JH, Campbell BJ, Pritchard DM. A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide. Dis Model Mech. 2013 Nov; 6(6):1388-99. PMID: 24046352.
      View in: PubMed
    28. Bernard JK, McCann SP, Bhardwaj V, Washington MK, Frey MR. Neuregulin-4 is a survival factor for colon epithelial cells both in culture and in vivo. J Biol Chem. 2012 Nov 16; 287(47):39850-8. PMID: 23033483.
      View in: PubMed
    29. Al Alam D, Sala FG, Baptista S, Galzote R, Danopoulos S, Tiozzo C, Gage P, Grikscheit T, Warburton D, Frey MR, Bellusci S. FGF9-Pitx2-FGF10 signaling controls cecal formation in mice. Dev Biol. 2012 Sep 15; 369(2):340-8. PMID: 22819677.
      View in: PubMed
    30. Hilliard VC, Frey MR, Dempsey PJ, Peek RM, Polk DB. TNF-a converting enzyme-mediated ErbB4 transactivation by TNF promotes colonic epithelial cell survival. Am J Physiol Gastrointest Liver Physiol. 2011 Aug; 301(2):G338-46. PMID: 21617117.
      View in: PubMed
    31. Yamaoka T, Frey MR, Dise RS, Bernard JK, Polk DB. Specific epidermal growth factor receptor autophosphorylation sites promote mouse colon epithelial cell chemotaxis and restitution. Am J Physiol Gastrointest Liver Physiol. 2011 Aug; 301(2):G368-76. PMID: 21617115.
      View in: PubMed
    32. Hobbs SS, Goettel JA, Liang D, Yan F, Edelblum KL, Frey MR, Mullane MT, Polk DB. TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2011 Aug; 301(2):G220-9. PMID: 21566012.
      View in: PubMed
    33. Rosen MJ, Frey MR, Washington MK, Chaturvedi R, Kuhnhein LA, Matta P, Revetta FL, Wilson KT, Polk DB. STAT6 activation in ulcerative colitis: a new target for prevention of IL-13-induced colon epithelial cell dysfunction. Inflamm Bowel Dis. 2011 Nov; 17(11):2224-34. PMID: 21308881.
      View in: PubMed
    34. Frey MR, Carraro G, Batra RK, Polk DB, Warburton D. Sprouty keeps bowel kinases regular in colon cancer, while miR-21 targets Sprouty. Cancer Biol Ther. 2011 Jan 01; 11(1):122-4. PMID: 21124074.
      View in: PubMed
    35. Frey MR, Hilliard VC, Mullane MT, Polk DB. ErbB4 promotes cyclooxygenase-2 expression and cell survival in colon epithelial cells. Lab Invest. 2010 Oct; 90(10):1415-24. PMID: 20585313.
      View in: PubMed
    36. Nagy TA, Frey MR, Yan F, Israel DA, Polk DB, Peek RM. Helicobacter pylori regulates cellular migration and apoptosis by activation of phosphatidylinositol 3-kinase signaling. J Infect Dis. 2009 Mar 01; 199(5):641-51. PMID: 19199544.
      View in: PubMed
    37. Frey MR, Edelblum KL, Mullane MT, Liang D, Polk DB. The ErbB4 growth factor receptor is required for colon epithelial cell survival in the presence of TNF. Gastroenterology. 2009 Jan; 136(1):217-26. PMID: 18973758.
      View in: PubMed
    38. McElroy SJ, Frey MR, Yan F, Edelblum KL, Goettel JA, John S, Polk DB. Tumor necrosis factor inhibits ligand-stimulated EGF receptor activation through a TNF receptor 1-dependent mechanism. Am J Physiol Gastrointest Liver Physiol. 2008 Aug; 295(2):G285-93. PMID: 18467504.
      View in: PubMed
    39. Dise RS, Frey MR, Whitehead RH, Polk DB. Epidermal growth factor stimulates Rac activation through Src and phosphatidylinositol 3-kinase to promote colonic epithelial cell migration. Am J Physiol Gastrointest Liver Physiol. 2008 Jan; 294(1):G276-85. PMID: 17991704.
      View in: PubMed
    40. Chen X, Abair TD, Ibanez MR, Su Y, Frey MR, Dise RS, Polk DB, Singh AB, Harris RC, Zent R, Pozzi A. Integrin alpha1beta1 controls reactive oxygen species synthesis by negatively regulating epidermal growth factor receptor-mediated Rac activation. Mol Cell Biol. 2007 May; 27(9):3313-26. PMID: 17339338.
      View in: PubMed
    41. Frey MR, Dise RS, Edelblum KL, Polk DB. p38 kinase regulates epidermal growth factor receptor downregulation and cellular migration. EMBO J. 2006 Dec 13; 25(24):5683-92. PMID: 17139251.
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    42. Ho SB, Dvorak LA, Moor RE, Jacobson AC, Frey MR, Corredor J, Polk DB, Shekels LL. Cysteine-rich domains of muc3 intestinal mucin promote cell migration, inhibit apoptosis, and accelerate wound healing. Gastroenterology. 2006 Nov; 131(5):1501-17. PMID: 17101324.
      View in: PubMed
    43. Frey MR, Golovin A, Polk DB. Epidermal growth factor-stimulated intestinal epithelial cell migration requires Src family kinase-dependent p38 MAPK signaling. J Biol Chem. 2004 Oct 22; 279(43):44513-21. PMID: 15316018.
      View in: PubMed
    44. Frey MR, Clark JA, Bateman NW, Kazanietz MG, Black AR, Black JD. Cell cycle- and protein kinase C-specific effects of resiniferatoxin and resiniferonol 9,13,14-ortho-phenylacetate in intestinal epithelial cells. Biochem Pharmacol. 2004 May 15; 67(10):1873-86. PMID: 15130764.
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    45. Clark JA, Black AR, Leontieva OV, Frey MR, Pysz MA, Kunneva L, Woloszynska-Read A, Roy D, Black JD. Involvement of the ERK signaling cascade in protein kinase C-mediated cell cycle arrest in intestinal epithelial cells. J Biol Chem. 2004 Mar 05; 279(10):9233-47. PMID: 14670956.
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    46. Frey MR, Leontieva O, Watters DJ, Black JD. Stimulation of protein kinase C-dependent and -independent signaling pathways by bistratene A in intestinal epithelial cells. Biochem Pharmacol. 2001 May 01; 61(9):1093-100. PMID: 11301042.
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    47. Frey MR, Clark JA, Leontieva O, Uronis JM, Black AR, Black JD. Protein kinase C signaling mediates a program of cell cycle withdrawal in the intestinal epithelium. J Cell Biol. 2000 Nov 13; 151(4):763-78. PMID: 11076962.
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    48. Verstovsek G, Byrd A, Frey MR, Petrelli NJ, Black JD. Colonocyte differentiation is associated with increased expression and altered distribution of protein kinase C isozymes. Gastroenterology. 1998 Jul; 115(1):75-85. PMID: 9649461.
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    49. Frey MR, Saxon ML, Zhao X, Rollins A, Evans SS, Black JD. Protein kinase C isozyme-mediated cell cycle arrest involves induction of p21(waf1/cip1) and p27(kip1) and hypophosphorylation of the retinoblastoma protein in intestinal epithelial cells. J Biol Chem. 1997 Apr 04; 272(14):9424-35. PMID: 9083081.
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