Description of Research Expertise:
1. Mechanisms of intestinal metaplasia of the esophagus (Barrett’s esophagus) and stomach, with a focus on developing novel cell culture and animal models for this disorder.
2. Role of myeloid derived suppressor cells in the pathogenesis of barrett’s esophagus and esophageal adenocarcinoma.
3. autophagy in the pathogenesis of Barrett’s esophagus, progression to neoplasia, and resistance to therapies.
4. Modeling the effects of Cox-2 activity on oxidative stress and DNA damage in the esophagus.
5. Identification of cells and factors contributing to the intestinal stem cell niche, and their response to injury and disease conditions.
6. Live-cell imaging studies of intestinal stem cell and crypt niche cell interactions, crypt fissioning, mitosis, and early events in neoplastic transformation by confocal microscopy.
Description of Research
Barrett’s Esophagus Focus:
Esophageal adenocarcinoma (EAC) has been the fastest rising malignancy in the U.S.. Several conditions increase the risk for the development of EAC, including obesity, smoking, diet, acid reflux, and, most significantly, Barrett's esophagus (BE). BE occurs at the gastroesophageal (GE) junction and is the replacement of normal squamous esophageal mucosa with an intestinalized columnar epithelium. It typically arises in response to chronic acid exposure and is associated with acid reflux. Importantly, the histologic precursor lesions and molecular mechanisms underpinning BE pathogenesis remain poorly understood. One reason is the paucity of experimental models for BE. Our research has focused on this problem, and the development of innovative, genetically based and physiologically relevant human cell based 3D organotypic cultures and transgenic mouse models for BE is an important objective of my lab. We are broadly pursuing several strategies including exploring the role proinflammatory cytokines (IL-1beta), eicosanoids (Cox-2), myeloid derived suppressor cells, and autophagy in BE pathogenesis and progression to neoplasia.
Intestinal Stem Cell Focus:
Stem cells are defined by the capacity for long-term self-renewal and multilineage differentiation. Until relatively recently, our understanding of stem cell biology, as well as their role in many human disease processes from aging to cancer, has been rather limited. Moreover, interest in harnessing the stem cell’s capacity for self-renewal to promote organ and tissue regeneration cuts across many medical disciplines. Genetic studies have identified several robust markers for stem cell populations in the intestine. These advances now make it possible to isolate stem cell populations for more advanced molecular investigations and ex vivo culture. We are presently developing human multi-cell based 3D culture systems in which we can model inflammatory conditions of the gut as a method of studying physiologically the effects of immune cells, inflammatory microenvironment, oxidative stress and mitochondrial dysfunction on stem cell biology and stem cell DNA damage. Recently we have also begin using live cell confocal microscopy to investigate how the intestinal stem cell niche is established, the relationship between niche and stem cells, how intestinal crypts fission, how stem cells undergo mitosis, and early events in neoplastic transformation.
Rotation students invited to discuss projects
Mary Ann Crissey--Research Specialist and Lab Manager
Jianping Kong PhD--Senior research Investigator
James Bortner PhD--Post Doctoral FellowDoctoral Fellow
Kira Hartman PhD--Post Doctoral FellowDoctoral Fellow
Fang Wang PhD--Post Doctoral Fellow
1. Stairs, D. B., Nakagawa, H., Klein-Szanto, A., Mitchell, S., Silberg, D., Tobias, J.W., Lynch, J. P., Rustgi, A. K.; “Cdx1 and c-myc foster the initiation of transdifferentiation of the normal esophageal squamous epithelium toward Barrett's Esophagus” PloS ONE 2008;3(10):e3534; PMCID: PMC2568822.
2. Huo, X., Zhang, H.Y., Zhang, X., Lynch, J.P., Strauch, E.D., Wang, J.Y., Hormi-Carver, K., Spechler, S.J., Souza, R.F.; “Differences in CDX-2 Expression after Exposure to Acid and Bile Salts in Esophageal Squamous Cell Lines from GERD Patients with and without Barrett’s Esophagus.” Gastroenterology 2010 Jul;139(1):194-203.e1 PMCID: PMC2902607
3. Funakoshi, S., Kong, J., Crissey, M.S., Dang, D., Dang, L., Lynch, J.P; “Cdx2 induces E-cadherin function by promoting E-cadherin localization to the cell surface” Am J Gastrointest Liver Physiol. (Editorial Highlight) 2010 Nov;299(5):G1054-67. PMCID: PMC2993167
4. Verzi, M.P., Hatzis, P., Philips, J., Sulahian, R., Schuijers, J., Freed, E., Brown, M.A., Lynch, J.P., Dang, D.T., Clevers, H., Liu, X.S., Shivdasani, R.A.; “TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis-elements” Proc Natl Acad Sci USA 2010 Aug 24;107(34):15157-62. PMCID: PMC2930576
5. Stairs, D.B., Kong, J., Lynch, J.P.; “Cdx genes, inflammation, and the pathogenesis of intestinal metaplasias” in “Molecular Biology of Digestive Organs.” Editor: Klaus Kaestner. Series Progress in Molecular Biology and Translational Science. 2010;96:231-70. PMID:21075347
6. Crissey, M.S., Guo, R.J., Funakoshi, S., Liu, J., Kong, J., Lynch, J.P.: "Cdx2 Levels Modulate Intestinal Epithelium Maturity and Paneth Cell Development". Gastroenterology 140(2): 517-528, 2011 Notes: Editor's pick for the February 2011 issue. PMCID: PMC3031739
7. Kong, J., Crissey, M.S., Funakoshi, S., Kreindler, J.L., and Lynch, J.P.: "Ectopic Cdx2 expression in murine esophagus models early events in Barrett's esophagus. " PloS ONE 6(4): e18280, April 2011. PMCID: PMC3071814
8. Kong, J., Crissey, M.S., Stairs, D.B., Sepulveda, A.R., and Lynch, J.P.: Cox2 and β-catenin/TCF signaling intestinalize human esophageal keratinocytes when cultured under organotypic conditions. Neoplasia 2011 Sep;13(9):792-805. PMCID: PMC3182272
9. Kong, J., Crissey, M.S., Sepulveda, A.R., and Lynch, J.P.: Math1/Atoh1 contributes to intestinalization of esophageal keratinocytes by inducing the expression of Muc2 and Keratin-20. Digestive Diseases and Sciences 57(4): 845-857; 2012 PMCID: PMC3407817 [Available on 2013/4/1]
10. McAfee, Q.; Zhang, Z.; Samanta, A.; Levi, S.; Ma, X., Piao, S.; Lynch, J.P.; Uhera, T.; Sepulveda, A.R.; Davis, L.; Winkler, J.D.; Amaravadi, R.K.: A novel autophagy inhibitor with single agent antitumor activity reproduces the phenotype of a genetic autophagy deficiency Proceedings of the National Academy of Science 2012 PMCID: PMC3361415
11. Stelzner, M., Helmrath, M., Dunn, J.C.Y., Henning, S.J., Houchen, C.W., Kuo, C., Lynch, J.P., Li, L., Magness, S.T., Martin, M.G., Wong, M., Yu, J. for the NIH Intestinal Stem Cell Consortium: A Nomenclature for Intestinal In Vitro Cultures. American J. Phys, Gastrointestinal and Liver April 2012 2012 Jun;302(12):G1359-63 PMCID: PMC3378093
12. Hamilton, K. E., Crissey, M.S., Lynch, J.P., Rustgi, A.K.: Culturing adult stem cells from mouse small intestinal crypts Cold Spring Harbor Laboratory Press. (2014)
13. Magness ST, Puthoff BJ, Crissey MA, Dunn J, Henning SJ, Houchen C, Kaddis JS, Kuo CJ, Li L, Lynch J, Martin MG, May R, Niland JC, Olack B, Qian D, Stelzner M, Swain JR, Wang F, Wang J, Wang X, Yan K, Yu J, Wong MH. “A multi-center study to standardize reporting and analyses of fluorescence-activated cell sorted murine intestinal epithelial cells.” American Journal of Physiology: Gastrointestinal and Liver Physiology.
2013. Oct;305(8):G542-51 PMCID:3798732
14. Hartman KG, Bortner JD, Falk GW, Yu J, Martín MG, Rustgi AK, Lynch JP. “Modeling inflammation and oxidative stress in gastrointestinal disease development using novel organotypic culture systems.” Stem Cell Res Ther. 2013;4 Suppl 1:S5. PMCID: PMC3983655
15. Hartman KG, Bortner JD, Falk GW, Ginsberg GG, Jhala N, Yu J, Martín MG, Rustgi AK, Lynch JP. “Modeling human gastrointestinal inflammatory diseases using microphysiological culture systems.” Exp Biol Med. 2014 Apr 29. PMCID pending NIHMSID # 603683
16. Vega ME, Giroux V, Natsuizaka M, Liu JM, Klein- Szanto AJ, Stairs DB, Nakagawa H, Wang KK, Wang TC, Lynch JP, Rustgi AK. “Inhibition of Notch signaling enhances transdifferentiation of the esophageal squamous epithelium towards a Barrett’s-like metaplasia via KLF4” Accepted for publication in Cell Cycle June 2014 PMCID pending
Xiao F, Crissey MS, Lynch JP, Silberg DG, Suh ER: Intestinal Metaplasia with a High-Salt Diet Induces Epithelial Proliferation and Alters Cell Composition in the Gastric Mucosa of Mice. Cancer Biol Ther 6 (4): 669-75,2005.
Lynch JP, and Rustgi AK: Mechanisms of GI Malignancies Physiology of the Gastrointestinal Tract, Johnson LR, Barret KE, Gishan FK, Merchant JL, Said HM. : 477-498,2006.
Ezaki T, Guo RJ, Reynolds A, Lynch JP: The Homeodomain Transcription Factors Cdx1 and Cdx2 Induce E-cadherin Adhesion Activity by Reducing beta- and p120-catenin Tyrosine Phosphorylation. Am J Physiol Gastrointest Liver Physiol 293 : G54-G65,2007.
Hegde SR, Sun W, and Lynch JP: Systemic and Targeted Therapy for Advanced Colon Cancer Expert Review in Gastroenterology and Hepatology 2 (1): 135-149,2008.
Kong J, Isariyawonse BK, Ezaki T, Nakagawa H, Silberg DG, and Lynch JP: Induction of Intestinalization in Human Esophageal Keratinocytes is a Multi-step Process Carcinogenesis 30 (1): 122-130,2009.
Stairs DB, Nakagawa H, Klein-Szanto A, Mitchell S, Silberg DG, Tobias JW, Lynch JP, Rustgi AK: Cdx1 and c-myc foster the initiation of transdifferentiation of the normal esophageal squamous epithelium toward Barrett's Esophagus PloS ONE 3 (10): e3534,2008.
Sepulveda AR, and Lynch JP: Chronic Inflammation and Genetic Instability in Gastrointestinal Cancers Cancer Genome and Tumor Microenvironment, Springer : P.351-398,2010.
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