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    Yicktung T Ip PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentProgram in Molecular Medicine
    AddressUniversity of Massachusetts Medical School
    373 Plantation Street
    Worcester MA 01605
    Phone508-856-5136
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - School of Medicine
      DepartmentCell and Developmental Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCell Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentProgram in Cell Dynamics

        Overview 
        Narrative

        Academic background

        Tony Ip received his BS from the National Defense Medical Center, Taipei, ROC in 1984 and his PhD from the University of Iowa in 1989. He was a Hoffmann-LaRoche Fellow of the Life Sciences Research Foundation from 1991-1994 at the University of California at San Diego. In 1994, he joined the University of Massachusetts Medical Center as assistant professor in the Program in Molecular Medicine. He was a recipient of a Scholar Award of the Leukemia Society of America in 1996-2001.

        Intestinal stem cells and tissue regeneration in Drosophila

        Dr. Tony Ip

        Humans and fruit flies do not look alike, yet many physiological processes in these two organisms share homologous molecules.We use Drosophila melanogaster, the common fruit fly, as a model organism to study the mechanisms by which intestinal stem cells respond to injury and initiate tissue repair. Around 1% of the US population experience inflammatory diseases of the intestine. Prolonged inflammation and tissue injury has also been proposed to potentiate gastrointestinal (GI) cancer. To understand how cells in the GI tract interact with wide varieties of microbes and pathogenic substances is important for developing therapeutic strategies that alleviate intestinal diseases. The human gastrointestinal tract is the major nutrient absorption organ that also has immune and endocrine function. It is also a major site for interaction with commensal bacteria and pathogenic substances. However, the human gastrointestinal tract is a relatively under-explored organ due to the complexity of the organ and the difficulty in experimental manipulation. Stem cell-mediated tissue repair is a promising approach for intestinal diseases. A major problem in intestinal stem cell research is that specific markers that can unambiguously identify these stem cells remain rare and the functions of these markers remain difficulty to study.

        My laboratory focuses on understanding how Drosophila intestinal stem cells mediate repair after tissue damage. Drosophila has emerged as a powerful tool for analyzing the function of human disease genes, either as fly homologues or by expressing in transgenic flies the mutated forms of human genes. Drosophila midgut is only 1 cm long and has a relatively simple cellular organization. Midgut intestinal stem cells have recently been identified that function to replenish the different cell types. We have demonstrated that these Drosophila intestinal stem cells can increase their division rate in response to tissue damage. Using this newly established system, we also show that intestinal stem cell division requires insulin signaling, a mechanism not yet shown in mammals thus suggesting that new information can be obtained from this system. To analyze how insulin and other regulatory pathways control intestinal stem cell division is our ongoing research direction. We have identified by transgenic expression assays and RNAi-based genetic screens a number of genes that are essential for damage-induced intestinal stem cell division. By studying the mechanisms of tissue damage-induced stem division in the genetically amenable Drosophila system, important insights will hopefully be obtained that can help to understand human stem cell-mediated tissue repair, intestinal inflammatory diseases and cancer progression.

        Figure1

        Figure Legend

        Cellular organization in adult Drosophila midgut. Left panel is DAPI staining for DNA in midgut. Right panel is a confocal image of midgut cross section. Phalloidin stains smooth muscle cells at the basal side and brush border of enterocytes at the lumenal side. Intestinal stem cells are some of the small cells located near the basal side. In adult Drosophila midgut, intestinal stem cell is the only cell type that divides and gives rise to all other cell types. We want to understand how the stem cell division is regulated, how the damaged epithelium is repaired, and how differentiation into various cell types is determined.




        Rotation Projects

        Rotation Projects

        Project #1: Mechanistic study of isolated mutants that show abnormal intestinal stem cell division phenotypes.

        Project #2:Perform transgenic RNAi-based genetic screen for genes required for intestinal stem cell response to tissue damage.



        Post Docs

        A postdoctoral position is available to study in this laboratory. Contact Dr. Ip for additional details.

        Bibliographic 
        selected publications
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        1. Li Q, Li S, Mana-Capelli S, Roth Flach RJ, Danai LV, Amcheslavsky A, Nie Y, Kaneko S, Yao X, Chen X, Cotton JL, Mao J, McCollum D, Jiang J, Czech MP, Xu L, Ip YT. The conserved misshapen-warts-yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila. Dev Cell. 2014 Nov 10; 31(3):291-304.
          View in: PubMed
        2. Amcheslavsky A, Song W, Li Q, Nie Y, Bragatto I, Ferrandon D, Perrimon N, Ip YT. Enteroendocrine cells support intestinal stem-cell-mediated homeostasis in Drosophila. Cell Rep. 2014 Oct 9; 9(1):32-9.
          View in: PubMed
        3. Yu S, Nie Y, Knowles B, Sakamori R, Stypulkowski E, Patel C, Das S, Douard V, Ferraris RP, Bonder EM, Goldenring JR, Ip YT, Gao N. TLR sorting by Rab11 endosomes maintains intestinal epithelial-microbial homeostasis. EMBO J. 2014 Sep 1; 33(17):1882-95.
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        4. Amcheslavsky A, Nie Y, Li Q, He F, Tsuda L, Markstein M, Ip YT. Gene expression profiling identifies the zinc-finger protein Charlatan as a regulator of intestinal stem cells in Drosophila. Development. 2014 Jul; 141(13):2621-32.
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        5. Zhou B, Yun EY, Ray L, You J, Ip YT, Lin X. Retromer promotes immune quiescence by suppressing spätzle-toll pathway in Drosophila. J Cell Physiol. 2014 Apr; 229(4):512-20.
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        6. Anjum SG, Xu W, Nikkholgh N, Basu S, Nie Y, Thomas M, Satyamurti M, Budnik BA, Ip YT, Veraksa A. Regulation of Toll Signaling and Inflammation by ß-Arrestin and the SUMO Protease Ulp1. Genetics. 2013 Dec; 195(4):1307-17.
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        7. Cheng W, Ip YT, Xu Z. Gudu, an Armadillo repeat-containing protein, is required for spermatogenesis in Drosophila. Gene. 2013 Dec 1; 531(2):294-300.
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        8. Ren F, Shi Q, Chen Y, Jiang A, Ip YT, Jiang H, Jiang J. Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration. Cell Res. 2013 Sep; 23(9):1133-46.
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        9. Nirala NK, Rahman M, Walls SM, Singh A, Zhu LJ, Bamba T, Fukusaki E, Srideshikan SM, Harris GL, Ip YT, Bodmer R, Acharya UR. Survival response to increased ceramide involves metabolic adaptation through novel regulators of glycolysis and lipolysis. PLoS Genet. 2013 Jun; 9(6):e1003556.
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        10. Amcheslavsky A, Ip YT. Be a good neighbor: organ-to-organ communication during the innate immune response. Cell Host Microbe. 2012 Apr 19; 11(4):323-4.
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        11. Kaneko S, Chen X, Lu P, Yao X, Wright TG, Rajurkar M, Kariya K, Mao J, Ip YT, Xu L. Smad inhibition by the Ste20 kinase Misshapen. Proc Natl Acad Sci U S A. 2011 Jul 5; 108(27):11127-32.
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        12. Amcheslavsky A, Ito N, Jiang J, Ip YT. Tuberous sclerosis complex and Myc coordinate the growth and division of Drosophila intestinal stem cells. J Cell Biol. 2011 May 16; 193(4):695-710.
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        13. Yagi Y, Nishida Y, Ip YT. Functional analysis of Toll-related genes in Drosophila. Dev Growth Differ. 2010 Dec; 52(9):771-83.
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        14. Ren F, Wang B, Yue T, Yun EY, Ip YT, Jiang J. Hippo signaling regulates Drosophila intestine stem cell proliferation through multiple pathways. Proc Natl Acad Sci U S A. 2010 Dec 7; 107(49):21064-9.
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        15. Chen S, Kaneko S, Ma X, Chen X, Ip YT, Xu L, Xie T. Lissencephaly-1 controls germline stem cell self-renewal through modulating bone morphogenetic protein signaling and niche adhesion. Proc Natl Acad Sci U S A. 2010 Nov 16; 107(46):19939-44.
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        16. Tanji T, Yun EY, Ip YT. Heterodimers of NF-kappaB transcription factors DIF and Relish regulate antimicrobial peptide genes in Drosophila. Proc Natl Acad Sci U S A. 2010 Aug 17; 107(33):14715-20.
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        17. Chatterjee M, Ip YT. Pathogenic stimulation of intestinal stem cell response in Drosophila. J Cell Physiol. 2009 Sep; 220(3):664-71.
          View in: PubMed
        18. Amcheslavsky A, Jiang J, Ip YT. Tissue damage-induced intestinal stem cell division in Drosophila. Cell Stem Cell. 2009 Jan 9; 4(1):49-61.
          View in: PubMed
        19. Xu L, Yao X, Chen X, Lu P, Zhang B, Ip YT. Msk is required for nuclear import of TGF-{beta}/BMP-activated Smads. J Cell Biol. 2007 Sep 10; 178(6):981-94.
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        20. Tanji T, Hu X, Weber AN, Ip YT. Toll and IMD pathways synergistically activate an innate immune response in Drosophila melanogaster. Mol Cell Biol. 2007 Jun; 27(12):4578-88.
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        21. Chen HB, Shen J, Ip YT, Xu L. Identification of phosphatases for Smad in the BMP/DPP pathway. Genes Dev. 2006 Mar 15; 20(6):648-53.
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        22. Yagi Y, Ip YT. Helicase89B is a Mot1p/BTAF1 homologue that mediates an antimicrobial response in Drosophila. EMBO Rep. 2005 Nov; 6(11):1088-94.
          View in: PubMed
        23. Ip YT. Drosophila innate immunity goes viral. Nat Immunol. 2005 Sep; 6(9):863-4.
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        24. Ganguly A, Jiang J, Ip YT. Drosophila WntD is a target and an inhibitor of the Dorsal/Twist/Snail network in the gastrulating embryo. Development. 2005 Aug; 132(15):3419-29.
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        25. Tanji T, Ip YT. Regulators of the Toll and Imd pathways in the Drosophila innate immune response. Trends Immunol. 2005 Apr; 26(4):193-8.
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        26. Craig CR, Fink JL, Yagi Y, Ip YT, Cagan RL. A Drosophila p38 orthologue is required for environmental stress responses. EMBO Rep. 2004 Nov; 5(11):1058-63.
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        27. Ashraf SI, Ganguly A, Roote J, Ip YT. Worniu, a Snail family zinc-finger protein, is required for brain development in Drosophila. Dev Dyn. 2004 Oct; 231(2):379-86.
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        28. Bettencourt R, Asha H, Dearolf C, Ip YT. Hemolymph-dependent and -independent responses in Drosophila immune tissue. J Cell Biochem. 2004 Jul 1; 92(4):849-63.
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        29. Hu X, Yagi Y, Tanji T, Zhou S, Ip YT. Multimerization and interaction of Toll and Spätzle in Drosophila. Proc Natl Acad Sci U S A. 2004 Jun 22; 101(25):9369-74.
          View in: PubMed
        30. Hemavathy K, Hu X, Ashraf SI, Small SJ, Ip YT. The repressor function of snail is required for Drosophila gastrulation and is not replaceable by Escargot or Worniu. Dev Biol. 2004 May 15; 269(2):411-20.
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        31. Bettencourt R, Ip YT. Learning the codes of fly immunity. Mol Cell. 2004 Jan 16; 13(1):1-2.
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        32. Bettencourt R, Tanji T, Yagi Y, Ip YT. Toll and Toll-9 in Drosophila innate immune response. J Endotoxin Res. 2004; 10(4):261-8.
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        33. Ip YT, Gridley T. Cell movements during gastrulation: snail dependent and independent pathways. Curr Opin Genet Dev. 2002 Aug; 12(4):423-9.
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        34. Lehmann M, Jiang C, Ip YT, Thummel CS. AP-1, but not NF-kappa B, is required for efficient steroid-triggered cell death in Drosophila. Cell Death Differ. 2002 May; 9(5):581-90.
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        35. Ooi JY, Yagi Y, Hu X, Ip YT. The Drosophila Toll-9 activates a constitutive antimicrobial defense. EMBO Rep. 2002 Jan; 3(1):82-7.
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        36. Ashraf SI, Ip YT. The Snail protein family regulates neuroblast expression of inscuteable and string, genes involved in asymmetry and cell division in Drosophila. Development. 2001 Dec; 128(23):4757-67.
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        37. Guru SC, Prasad NB, Shin EJ, Hemavathy K, Lu J, Ip YT, Agarwal SK, Marx SJ, Spiegel AM, Collins FS, Oliver B, Chandrasekharappa SC. Characterization of a MEN1 ortholog from Drosophila melanogaster. Gene. 2001 Jan 24; 263(1-2):31-8.
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        38. Hemavathy K, Ashraf SI, Ip YT. Snail/slug family of repressors: slowly going into the fast lane of development and cancer. Gene. 2000 Oct 17; 257(1):1-12.
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        39. Hemavathy K, Guru SC, Harris J, Chen JD, Ip YT. Human Slug is a repressor that localizes to sites of active transcription. Mol Cell Biol. 2000 Jul; 20(14):5087-95.
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        40. Ashraf SI, Hu X, Roote J, Ip YT. The mesoderm determinant snail collaborates with related zinc-finger proteins to control Drosophila neurogenesis. EMBO J. 1999 Nov 15; 18(22):6426-38.
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        41. Han ZS, Ip YT. Interaction and specificity of Rel-related proteins in regulating Drosophila immunity gene expression. J Biol Chem. 1999 Jul 23; 274(30):21355-61.
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        42. Meng X, Khanuja BS, Ip YT. Toll receptor-mediated Drosophila immune response requires Dif, an NF-kappaB factor. Genes Dev. 1999 Apr 1; 13(7):792-7.
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        43. Ashraf SI, Ip YT. Transcriptional control: repression by local chromatin modification. Curr Biol. 1998 Sep 24; 8(19):R683-6.
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        44. Han ZS, Enslen H, Hu X, Meng X, Wu IH, Barrett T, Davis RJ, Ip YT. A conserved p38 mitogen-activated protein kinase pathway regulates Drosophila immunity gene expression. Mol Cell Biol. 1998 Jun; 18(6):3527-39.
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        45. Ip YT, Davis RJ. Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development. Curr Opin Cell Biol. 1998 Apr; 10(2):205-19.
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        46. Hemavathy K, Meng X, Ip YT. Differential regulation of gastrulation and neuroectodermal gene expression by Snail in the Drosophila embryo. Development. 1997 Oct; 124(19):3683-91.
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        47. Ip YT, Hemavathy K. Drosophila development. Delimiting patterns by repression. Curr Biol. 1997 Apr 1; 7(4):R216-8.
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        48. Sluss HK, Han Z, Barrett T, Goberdhan DC, Wilson C, Davis RJ, Ip YT. A JNK signal transduction pathway that mediates morphogenesis and an immune response in Drosophila. Genes Dev. 1996 Nov 1; 10(21):2745-58.
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        49. Petersen UM, Björklund G, Ip YT, Engström Y. The dorsal-related immunity factor, Dif, is a sequence-specific trans-activator of Drosophila Cecropin gene expression. EMBO J. 1995 Jul 3; 14(13):3146-58.
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        50. Tatei K, Cai H, Ip YT, Levine M. Race: a Drosophila homologue of the angiotensin converting enzyme. Mech Dev. 1995 Jun; 51(2-3):157-68.
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        51. Ip YT. Transcriptional regulation. Converting an activator into a repressor. Curr Biol. 1995 Jan 1; 5(1):1-3.
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        52. Ip YT, Maggert K, Levine M. Uncoupling gastrulation and mesoderm differentiation in the Drosophila embryo. EMBO J. 1994 Dec 15; 13(24):5826-34.
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        53. Ip YT, Levine M. Molecular genetics of Drosophila immunity. Curr Opin Genet Dev. 1994 Oct; 4(5):672-7.
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        54. Ip YT, Levine M, Bier E. Neurogenic expression of snail is controlled by separable CNS and PNS promoter elements. Development. 1994 Jan; 120(1):199-207.
          View in: PubMed
        55. Ip YT, Reach M, Engstrom Y, Kadalayil L, Cai H, González-Crespo S, Tatei K, Levine M. Dif, a dorsal-related gene that mediates an immune response in Drosophila. Cell. 1993 Nov 19; 75(4):753-63.
          View in: PubMed
        56. Ip YT, Park RE, Kosman D, Bier E, Levine M. The dorsal gradient morphogen regulates stripes of rhomboid expression in the presumptive neuroectoderm of the Drosophila embryo. Genes Dev. 1992 Sep; 6(9):1728-39.
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        57. Ip YT, Park RE, Kosman D, Yazdanbakhsh K, Levine M. dorsal-twist interactions establish snail expression in the presumptive mesoderm of the Drosophila embryo. Genes Dev. 1992 Aug; 6(8):1518-30.
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        58. Ip YT, Levine M, Small SJ. The bicoid and dorsal morphogens use a similar strategy to make stripes in the Drosophila embryo. J Cell Sci Suppl. 1992; 16:33-8.
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        59. Kosman D, Ip YT, Levine M, Arora K. Establishment of the mesoderm-neuroectoderm boundary in the Drosophila embryo. Science. 1991 Oct 4; 254(5028):118-22.
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        60. Jiang J, Kosman D, Ip YT, Levine M. The dorsal morphogen gradient regulates the mesoderm determinant twist in early Drosophila embryos. Genes Dev. 1991 Oct; 5(10):1881-91.
          View in: PubMed
        61. Ip YT, Kraut R, Levine M, Rushlow CA. The dorsal morphogen is a sequence-specific DNA-binding protein that interacts with a long-range repression element in Drosophila. Cell. 1991 Jan 25; 64(2):439-46.
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        62. Ip YT, Poon D, Stone D, Granner DK, Chalkley R. Interaction of a liver-specific factor with an enhancer 4.8 kilobases upstream of the phosphoenolpyruvate carboxykinase gene. Mol Cell Biol. 1990 Jul; 10(7):3770-81.
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        63. Ip YT, Fournier RE, Chalkley R. Extinction of phosphoenolpyruvate carboxykinase gene expression is associated with loss of a specific chromatin-binding protein from a far upstream domain. Mol Cell Biol. 1990 Jul; 10(7):3782-7.
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        64. Ip YT, Granner DK, Chalkley R. Hormonal regulation of phosphoenolpyruvate carboxykinase gene expression is mediated through modulation of an already disrupted chromatin structure. Mol Cell Biol. 1989 Mar; 9(3):1289-97.
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