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dc.contributor.authorHoutz, Philip Lewis
dc.date.accessioned2019-04-02T14:00:10Z
dc.date.available2019-07-02T06:01:43Z
dc.date.issued2018-12-30
dc.identifier.otherHoutz_cornellgrad_0058F_11172
dc.identifier.otherhttp://dissertations.umi.com/cornellgrad:11172
dc.identifier.otherbibid: 10758009
dc.identifier.urihttps://hdl.handle.net/1813/64869
dc.description.abstractThe epithelium of the gastrointestinal (GI) tract serves vital roles as both digestive tissue and a barrier against pathogens and other harmful material from the environment. In order to maintain homeostasis, intestinal epithelia must undergo continuous tissue turnover by the activity of dedicated intestinal stem cells (ISCs), which divide to self-renew and differentiate into new epithelial cells. Regulating constant tissue renewal in spite of physical and microbial challenges requires careful coordination by cellular signaling to link the detection of damage or stress with adequate repair. In this thesis, I investigated the regulatory networks controlling intestinal epithelial cell behavior to promote repair of infectious damage in the midgut of Drosophila melanogaster. In both healthy and diseased conditions, pro-regenerative cytokines function as central coordinators of gut renewal, linking inflammation to stem cell activity. In Drosophila, the primary reparative cytokine, Unpaired 3 (Upd3), serves to stimulate the JAK/STAT pathway in epithelial cells in response to pathogenic damage. In the beginning of my PhD, I familiarized myself with the tools and techniques associated with the study of Drosophila midgut repair. The details of these procedures were compiled and published as a chapter in Methods in Molecular Biology, Animal Models for Stem Cell Therapy. I then began an investigation of the regulation of cytokine activity in the Drosophila midgut. I found that the transcriptional activation of upd3 in midgut enterocytes is regulated by the Hippo, Src-MAPK, and TGF-B pathways, which are known to be similarly active in ISCs following enteric damage, and required for subsequent repair responses. This work was published in PLOS Genetics in 2017. Following my findings of the regulatory pathways that initiate epithelial repair in the adult midgut, I investigated how the larval Drosophila midgut, which lacks dedicated ISCs and basal tissue turnover, is able to cope with bacteria-induced damage. Larval Drosophila were found to be more susceptible to infection, and survivors experienced a developmental delay in the onset of pupation. Infected larvae that survive to reach pupation experienced no further delay in their development rate to adult eclosion, and experience no lasting negative impact on their lifespan. I discovered that the larval midgut epithelium was able to undergo limited repair following enteric infection-induced cell loss, by temporary recruitment of adult midgut progenitor (AMP) cells to be differentiated into new enterocytes. Fascinatingly, I found that AMP differentiation in response to epithelial damage is also regulated by Upd3 and the JAK/STAT pathway. In addition to the aforementioned publications, I collaborated with DJ Dutta of Bruce Edgars lab as a middle author in her 2015 Cell Reports paper. Altogether, my work has identified key regulatory networks that act to control epithelial renewal in the GI tract. I have found that JAK/STAT, Notch, EGFR and TGF-B/Dpp signaling pathways are activated in multiple epithelial cell types following pathogenic damage to gut tissue. Interestingly, the activation of these pathways directs both conventional, ISC-mediated tissue repair, as well as alternative methods of regeneration during development, in the absence of dedicated ISCs. This suggests that these pathways serve a conserved function to initiate healing in response to enteric infections, but are nonetheless dynamic in the means by which this is accomplished under different sets of constraints.
dc.language.isoen_US
dc.rightsAttribution-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nd/4.0/
dc.subjectCellular biology
dc.subjectBacterial infection
dc.subjectGenetic network
dc.subjectIntestinal Stem Cell
dc.subjectTissue repair
dc.subjectGenetics
dc.subjectDrosophila melanogaster
dc.subjectEntomology
dc.titleCHARACTERIZATION OF MIDGUT EPITHELIAL REPAIR IN ADULT AND LARVAL DROSOPHILA IN RESPONSE TO ENTERIC INFECTION
dc.typedissertation or thesis
thesis.degree.disciplineEntomology
thesis.degree.grantorCornell University
thesis.degree.levelDoctor of Philosophy
thesis.degree.namePh. D., Entomology
dc.contributor.chairBuchon, Nicolas S.
dc.contributor.committeeMemberLeifer, Cynthia Anne
dc.contributor.committeeMemberLazzaro, Brian
dc.contributor.committeeMemberKurpios, Natasza
dcterms.licensehttps://hdl.handle.net/1813/59810
dc.identifier.doihttps://doi.org/10.7298/hstf-gk41


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