Postdoctoral Position Available

Tony Ip, Ph.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Program in Molecular Medicine

Other Affiliation(s):
   Cell Biology
   Cell Dynamics Group
   Interdisciplinary Graduate Program

Intestinal stem cells and tissue regeneration in Drosophila

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.

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.

Recent Publications

Sluss, H. K., Han, Z., Berette, T., Goberdhan, D. C. I., Wilson, C., Davis, R. J., and Ip, Y. T. (1996) A JNK signal transduction pathway that mediates morphogenesis and an immune response in Drosophila. Genes and Development 10: 2745-2758.

Hemavathy, K., Meng, X., and Ip, Y. T. (1997) Differential regulation of gastrulation and neuroectodermal gene expression by Snail in the Drosophila embryo. Development 124: 3683-3691.

Han, Z. S., Enslen, H., Hu, X., Meng, X., Wu, I. H., Berette, T., Davis, R. J., and Ip, Y. T. (1998) A conserved p38 MAP kinase pathway regulates Drosophila immunity gene expression. Mol. Cell. Biol. 18: 3527-3539.

Meng, X, Khanuja, B., and Ip, Y. T. (1999) The Toll receptor-mediated Drosophila immune response requires Dif, an NF-kB factor. Genes and Development 13: 792-797.

Hemavathy, K., Guru, S. C., Harris, J., Chen, J. D. and Ip, Y. T. (2000) Human Slug is a transcriptional repressor that modulates transcription at sites where activation occurs. Mol. Cell. Biol. 20: 5087-5095.

Ashraf, S. I. and Ip, Y. T. (2001) The Snail family of proteins regulate neuroblast expression of inscuteable and string, genes involved in asymmetry and cell division in Drosophila. Development. 128: 4757-4767.

Ooi, J. Y., Yagi, Y., Hu, X., and Ip, Y. T. (2002) The Drosophila Toll-9 activates a constitutive antimicrobial defense. EMBO Report. 3: 82-87.

Gilmore, T. D. and Ip, Y. T. (2003)  Signal Transduction Pathways in Development and Immunity: Rel Pathways. In: Nature Encyclopedia of Life Sciences. London: Nature Publishing Group, http://www.els.net/   doi:10.1038/npg.els.0002332. (Review)

Hemavathy,  K., Hu, X., Ashraf, S. I., Small, S., and Ip, Y. T. (2004)  The Snail repressor function is required for Drosophila gastrulation and is not replaceable by Worniu or Escargot.  Developmental Biology 269: 411-420. 

Bettencourt,  R. and Ip, Y.T. (2004)  Learning the codes of fly immunity.  Molecular Cell 13: 1-2.  (Preview)

Ashraf, S. I., Ganguly, A., Roote, J. and Ip, Y. T. (2004)  Worniu, a Snail family zinc-finger protein, is required for brain development in Drosophila.  Developmental Dynamics, 231: 379-386. 

Hu, X., Yagi, Y., Tanji, T., Zhou, S., and Ip, Y.T. (2004)  Multimerization and interaction of Toll and Spatzle in Drosophila.  Proc. Natl. Acad. Sci. USA. 101: 9369-9374.

Bettencourt,  R. Asha, H., Dearolf, C., and Ip, Y.T.  (2004)  Hemolymph-dependent and -independent responses to microbial substances in Drosophila.  J. Cell. Biochem. 92:849-863.

Bettencourt,  R., Tanji, T., Yagi, Y., and Ip, Y. T. (2004)  Toll and Toll-9 in Drosophila innate immune response.  J. Endotoxin Res.  10: 261-268. 

Wakabayashi-Ito, N. and Ip, Y.T.  (2004)  Mesoderm formation in the Drosophila embryo.  In:  Muscle Development in Drosophila. (Ed. H. Sink)  Landes Bioscience. (Book Chapter)

Craig, C. R., Fink, J. L., Yagi, Y.,  Ip, Y. T., and Cagan, R. L. (2004) A Drosophila p38 ortholog is required for environmental stress responses.  EMBO Reports 5: 1058-1063.

Tanji, T. and Ip, Y. T. (2005) Regulators of the Toll and Imd pathways in the Drosophila innate immune response.   Trends Immunol. 26:193-198.  (Review)

Ganguly, A. Jiang, J., and Ip, Y. T. (2005)  Drosophila WntD is a target and an inhibitor of the Dorsal/Twist/Snail network in the gastrulating embryo.  Development 132: 3419-3429.

Clem, K.W. and Ip, Y. T. (2005)  Nuclear Factor kappa B.  In: Gene Expression and Regulation (ed. J. Ma), Current Scientific Frontiers Book, Higher Education Press (Beijing ), in press.  (Book Chapter)

Ip, Y. T. (2005)  Drosophila innate immunity goes viral.  Nat. Immun. 6:863-864. (News and Views).

Yagi, Y. and Ip Y. T.  (2005)  Helicase89B is a Mot1p/BTAF1 homolog that mediates an antimicrobial response in Drosophila.   EMBO Reports 6:1088-1094.

Chen, H.B., Shen, J., Ip, Y. T. and Xu, L. (2006)   Identification of phosphatases for Smad in the BMP/DPP pathway.  Genes & Development 20: 648-653.

Tanji, T., Hu, X., Weber, A. and Ip , Y.T. (2007)  Toll and IMD pathways synergistically activate innate immune response in Drosophila.  Mol. Cell. Biol.  27: 4578-4583.

Xu, L., Yao, X., Chen. X., Lu, P., Zhang, B., and Ip, Y.T. (2007)  Msk is required for nuclear import of TGF-b/BMP-activated Smads.  J. Cell Biol. 178: 981-94.

Amcheslavsky, A. and Ip, Y.T. (2008) Drosophila as a model for intestinal diseases.  J. Medical Sciences 28: 187-192.  (review)

Amcheslavsky, A., Jiang, J., and Ip Y.T. (2009) Tissue damage-induced intestinal stem cell division in Drosophila.  Cell Stem Cell 4: 49-61.  (cover story)

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.

Laboratory Personnel

Post-Doctoral Fellows: Alla Amcheslavsky, Eun-Young Yun

Research Assistant: Najwa Mohammad, Guoqiang Wang

Graduate Student: Madhurima Chatterjee

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.

Office: Biotech II, rm109
Phone: 508-856-5136
E-mail: Tony.Ip@umassmed.edu
Keywords: Genetic Systems, Stem Cell Biology, Organisms - Drosophila

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