While it is established that the incidence of gastric ulcers in the elderly is primarily due to increased use of NSAIDs and other medications, and increased H. pylori infection, the tissue's ability to repair gastric injuries is impaired. Our impression that ulcers heal normally in the aged stomach is false. The available treatments for peptic ulcer are essentially based on gastric acid suppression with anti-secretory drugs and the eradication of H. pylori infection. Despite the evidence that shows ulcers and their complications are a burden that is focused in the elderly, there is a lack of knowledge as to the molecular mechanisms that disrupt repair even after H. pylori eradication within the aged stomach. The objectives of this proposal are to 1) develop an understanding for the process of gastric regeneration, and to then 2) identify the mechanism by which the basic aging process of the stomach leads to an epithelium incapable of repair in response to injury. The acquisition of such knowl- edge is the first step in a continuum of research required to achieve our long-term goal to understand the proc- ess of gastric epithelial repair in response to injury. The central hypothesis is that loss of Hedgehog signaling within the normal stem cell environment of the aged stomach results in impaired regeneration of the stomach in response to injury. The hypothesis has been formulated on the basis of preliminary data that show during re- pair of the stomach in response to ulceration there is the emergence of Spasmolytic Polypeptide/TFF2- Expressing Metaplasia (SPEM) cells at the base of ulcer margin. Our data suggest that SPEM represents the major reparative lineage responsible for wound healing after severe gastric ulcer injury. We have also identi- fied that the cell surface protein CD44, in particular its variant isoforms (CD44v), marks a population of cells within reparative SPEM glands that express Hedgehog receptor Patched (Ptch). Moreover, Hedgehog proteins Sonic Hedgehog (Shh) and Indian Hedgehog (Ihh) are key regulatory factors that play reparative roles in re- sponse to injury by regulating macrophage infiltration and CD44v expression, respectively. Guided by strong preliminary data, this hypothesis is tested by pursuing two specific aims: 1) what is the mechanism by which Hedgehog signaling regulates gastric epithelial repair? And, 2) what is the mechanism by which the aging process of the stomach leads to disrupted repair? The hypothesis will be tested using bone marrow chimeras, heterochronic and isochronic parabioses, a mouse injury/transplantation model using mouse- and human- derived gastric organoids and lineage mapping experiments. At the completion of these studies, we expect to define the molecular events that are crucial for the repair of the gastric epithelium. Outcomes from the pro- posed studies are expected to have significantly advanced our current knowledge of the mechanism by which aging leads to disrupted epithelial repair. The rationale that underlies the research proposed is to develop the potential for testing therapeutic target efficacy and other strategies, such as stem-cell therapy, for the regen- eration of the aged stomach.

Public Health Relevance

While the incidence of peptic ulcer is decreasing in the general population, the rates of gastric and duodenal ulcer hospitalization and mortality remain high in older patients. At the completion of these studies it is ex- pected that we will 1) advance our understanding of the process of gastric regeneration, and to then 2) identify the mechanism by which the basic aging process of the stomach leads to an epithelium that is compromised and incapable of normal repair in response to injury. The outcomes are expected to benefit human health be- cause the studies will provide a mechanistic understanding of gastric epithelial repair to develop the potential for new therapeutic opportunities for the normal regeneration of the aged stomach.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK083402-06A1
Application #
9195543
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hamilton, Frank A
Project Start
2011-02-01
Project End
2020-04-30
Budget Start
2016-07-01
Budget End
2017-04-30
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Physiology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Zavros, Yana (2017) Initiation and Maintenance of Gastric Cancer: A Focus on CD44 Variant Isoforms and Cancer Stem Cells. Cell Mol Gastroenterol Hepatol 4:55-63
Bertaux-Skeirik, Nina; Wunderlich, Mark; Teal, Emma et al. (2017) CD44 variant isoform 9 emerges in response to injury and contributes to the regeneration of the gastric epithelium. J Pathol 242:463-475
Engevik, Amy C; Feng, Rui; Choi, Eunyoung et al. (2016) The Development of Spasmolytic Polypeptide/TFF2-Expressing Metaplasia (SPEM) During Gastric Repair Is Absent in the Aged Stomach. Cell Mol Gastroenterol Hepatol 2:605-624
Keilberg, Daniela; Zavros, Yana; Shepherd, Benjamin et al. (2016) Spatial and Temporal Shifts in Bacterial Biogeography and Gland Occupation during the Development of a Chronic Infection. MBio 7:
Konstantinou, Daniel; Bertaux-Skeirik, Nina; Zavros, Yana (2016) Hedgehog signaling in the stomach. Curr Opin Pharmacol 31:76-82
Dedhia, Priya H; Bertaux-Skeirik, Nina; Zavros, Yana et al. (2016) Organoid Models of Human Gastrointestinal Development and Disease. Gastroenterology 150:1098-1112
Bertaux-Skeirik, Nina; Centeno, Jomaris; Feng, Rui et al. (2016) Co-culture of Gastric Organoids and Immortalized Stomach Mesenchymal Cells. Methods Mol Biol 1422:23-31
Wroblewski, Lydia E; Piazuelo, M Blanca; Chaturvedi, Rupesh et al. (2015) Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells. Gut 64:720-30
Schumacher, Michael A; Aihara, Eitaro; Feng, Rui et al. (2015) The use of murine-derived fundic organoids in studies of gastric physiology. J Physiol 593:1809-27
Bertaux-Skeirik, Nina; Feng, Rui; Schumacher, Michael A et al. (2015) CD44 plays a functional role in Helicobacter pylori-induced epithelial cell proliferation. PLoS Pathog 11:e1004663

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