Targeting cyclic GMP signaling for the treatment of gastrointestinal diseases

Hdl Handle:
http://hdl.handle.net/10675.2/621679
Title:
Targeting cyclic GMP signaling for the treatment of gastrointestinal diseases
Authors:
Sharman, Sarah Kristen
Abstract:
Continual renewal of the luminal epithelium in the gut is essential for the maintenance of a healthy intestine as it sustains the barrier that protects underlying tissue from infiltration of material passing through the lumen. Dysregulation of homeostatic processes involved in maintenance of the barrier have been implicated in numerous gastrointestinal diseases. The cGMP signaling axis has emerged as an important regulator of homeostasis in the intestinal mucosa, and has been implicated in the suppression of visceral pain, colitis, and colon cancer. While there is considerable interest in exploiting this pathway, until recently the approaches used to increase cGMP have been limited. The present study sought to test the hypothesis that elevation of cGMP in the intestinal epithelium using PDE5 inhibitors will alter epithelial homeostasis and be therapeutic for constipation and preventative for colon cancer. Healthy mice treated with the PDE5 inhibitor sildenafil or the GC-C agonist linaclotide exhibited reduced proliferation and apoptosis, and increased numbers of differentiated secretory cells in the intestinal epithelium. In addition to these homeostatic effects, both drugs normalized intestinal transit and fecal water content in two mouse models of constipation. Furthermore, administration of sildenafil to mice treated with dextran sulfate sodium tightened the disrupted epithelial barrier. Treatment of ApcMin/+ mice with sildenafil or linaclotide significantly reduced the number of polyps per mouse (67% and 50%, respectively). The effect of these cGMP-elevating agents was not on the polyps themselves but was rather on the pre-neoplastic tissue, which was less proliferative and more apoptotic in the presence of the drugs. Taken together, the results of this study demonstrate that increasing cGMP with a pediatric dose of PDE5 inhibitors could be a potential alternative to GC-C agonists for the treatment of gastrointestinal diseases.
Affiliation:
Department of Biochemistry and Molecular Biology / Cancer Center
Issue Date:
25-Jan-2018
URI:
http://hdl.handle.net/10675.2/621679
Type:
Dissertation
Description:
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Appears in Collections:
Theses and Dissertations; Department of Cellular Biology and Anatomy Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorSharman, Sarah Kristen-
dc.date.accessioned2018-01-25T23:23:28Z-
dc.date.available2018-01-25T23:23:28Z-
dc.date.issued2018-01-25-
dc.identifier.urihttp://hdl.handle.net/10675.2/621679-
dc.descriptionThe file you are attempting to access is currently restricted to Augusta University. Please log in with your NetID if off campus.en
dc.description.abstractContinual renewal of the luminal epithelium in the gut is essential for the maintenance of a healthy intestine as it sustains the barrier that protects underlying tissue from infiltration of material passing through the lumen. Dysregulation of homeostatic processes involved in maintenance of the barrier have been implicated in numerous gastrointestinal diseases. The cGMP signaling axis has emerged as an important regulator of homeostasis in the intestinal mucosa, and has been implicated in the suppression of visceral pain, colitis, and colon cancer. While there is considerable interest in exploiting this pathway, until recently the approaches used to increase cGMP have been limited. The present study sought to test the hypothesis that elevation of cGMP in the intestinal epithelium using PDE5 inhibitors will alter epithelial homeostasis and be therapeutic for constipation and preventative for colon cancer. Healthy mice treated with the PDE5 inhibitor sildenafil or the GC-C agonist linaclotide exhibited reduced proliferation and apoptosis, and increased numbers of differentiated secretory cells in the intestinal epithelium. In addition to these homeostatic effects, both drugs normalized intestinal transit and fecal water content in two mouse models of constipation. Furthermore, administration of sildenafil to mice treated with dextran sulfate sodium tightened the disrupted epithelial barrier. Treatment of ApcMin/+ mice with sildenafil or linaclotide significantly reduced the number of polyps per mouse (67% and 50%, respectively). The effect of these cGMP-elevating agents was not on the polyps themselves but was rather on the pre-neoplastic tissue, which was less proliferative and more apoptotic in the presence of the drugs. Taken together, the results of this study demonstrate that increasing cGMP with a pediatric dose of PDE5 inhibitors could be a potential alternative to GC-C agonists for the treatment of gastrointestinal diseases.-
dc.subjectcGMPen
dc.subjectPDE5en
dc.subjectGC-C agonisten
dc.subjectIBSen
dc.subjectConstipationen
dc.subjectMotilityen
dc.subjectColon Canceren
dc.titleTargeting cyclic GMP signaling for the treatment of gastrointestinal diseases-
dc.typeDissertationen
dc.contributor.departmentDepartment of Biochemistry and Molecular Biology / Cancer Centeren
dc.language.rfc3066en-
dc.date.updated2018-01-25T23:23:28Z-
dc.description.advisorBrowning, Darrenen
dc.description.committeeLiu, Kebin; Maihle, Nita; McCluskey, Lynnette; Singh, Nagendraen
dc.description.degreeDoctor in Philosophy with a Major in Biochemistry and Cancer Biologyen
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