- Author
-
D. Straub
- Title
- Using the mouse to study Barrett’s Esophagus
- Subtitle
- We ain’t that different after all
- Supervisors
- Co-supervisors
-
K.B. Parikh
- Award date
- 12 February 2020
- Number of pages
- 169
- ISBN
- 9789463806237
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
The main risk factor for developing Barrett's esophagus (BE), a precursor of adenocarcinoma, is reflux. BE is defined as the replacement of normal esophageal epithelium with cylindrical (gastric or intestinal type) epithelium in the lower part of the esophagus. In a surgically induced reflux mouse model, we demonstrated that the presence of gastric-type metaplasia precedes further development into the intestinal type. Chronic inflammation results in upregulation of matrix metalloproteases, followed by activation of BMP4/pSMAD signaling resulting in intestinal factors such as CDX2 and MUC2.
In a mouse model we showed that over-expression of BMP4, or the deletion of its natural antagonist Noggin in the adult esophagus, causes development of multilayered glands (MLGs). These glands contain both squamous and gastric columnar cells, similar to columnar metaplasia. Subsequent blocking of the increased BMP levels with specific VHH antibodies, resulted in regeneration of the squamous cells, while blocking the columnar cells. Effective inhibition of BMP can be used to reverse BE and reduce the cancer risk of BE.
Bile acids play an important role in the progression from BE to adenocarcinoma. We demonstrated in mice that certain bile acids are more effective in inducing MLGs. The murine multilayered glands showed remarkable similarities, both structural and functional. Because it is suggested in humans that BE arises from submucosal glands, we assumed that in mice BE arises from MLGs. In the future this physiological reflux mouse model can be used to further unravel the molecular processes and find out the origin of BE. - Persistent Identifier
- https://hdl.handle.net/11245.1/ffd3b031-f961-419a-a623-2c50632d8515
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: General introduction
Chapter 2: Active matrix metalloproteases are expressed early on and are high during the Barrett’s Esophagus malignancy sequence
Chapter 3: A pSMAD/CDX2 complex is essential for the intestinalization of epithelial metaplasia
Chapter 4: Glycine-conjugated bile acids induce intestinal metaplasia in mice from multilayered glands through crypt fission
Chapter 5: Inhibition of BMP2 and BMP4 eradicates Barrett’s Esophagus and enhances the regeneration of squamous epithelium
Chapter 6: Summary and general discussion
Nederlandse samenvatting; Dankwoord; List of publications; Authors contribution per chapter; PhD portfolio; Curriculum vitae; List of abbreviations
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