Acute and chronic inflammatory environments of the gastrointestinal tract like gastroesophageal reflux disease (GERD), intestinal graft vs. host disease (GVHD), acute rejection after small intestine transplantation, and IBD conditions like Ulcerative colitis (UC), are fairly common human diseases. Disease models based on human cell and tissue culture systems that recapitulate in vivo growth and differentiation patterns would enhance our understanding of disease progression and improve prevention and detection strategies. This is an important objective of this proposal. In these disorders, epithelial cel oxidative stress is a key pathogenic factor for disease progression. This oxidative stress is partly from endogenous enzymes (Cyclooxygenases and NADPH oxidases) that induce DNA damage and mutations, and alter DNA methylation patterns, which together contributes to the development of metaplasia and cancer. We have begun to explore this using organotypic culture systems to model Cox-2 in BE pathogenesis. When we ectopically express Cox-2 in normal human esophageal keratinocytes, we observe the development of intestinal mucin-filled cysts. We propose to extend this success in physiologically relevant directions. Our main objective will be to test the hypothesis that the organotypic culture systems can be modified to model acute and chronic oxidative stress in esophageal and intestinal epithelium that physiologically resembles in vivo events in GERD, BE, GVHD, small bowel transplant rejection, and UC. We propose to test this by pursuing the following Specific Aims: 1) Adapt the esophageal organotypic culture system to better model GERD esophagitis and progression of stem cells to metaplasia and dysplasia. 2) Develop organotypic and 3D multi-cellular culture systems to model inflammatory microenvironments of GVHD, small bowel transplant rejection, and IBD including UC. GERD/BE, IBD/neoplasia, and GVHD are important, relatively common conditions that place a significant burden on the US healthcare system. We propose to develop novel multi-cellular in vitro human tissue engineered models that are representative of the pathogenesis for these conditions. These models will be of enormous value, allowing us to test hypotheses and advance our understanding of these disorders rapidly, and would have a translational impact since pharmacologic inhibition of Cox-2 is well established. This work will greatly improve our ability to study, prevent, and treat Barrett's esophagus, IBD, and GVHD. It will also foster the development of novel therapeutic and preventive strategies that will improve patient care for these important clinical conditions.

Public Health Relevance

Chronic inflammatory conditions are an especially burdensome healthcare problem in the US. Not only must the pain and disability be managed, but patients and health-care providers must be vigilant for the long-term consequences of chronic inflammation, most prominently cancer. Two examples of this are acid reflux disease, which leads to metaplasia and cancer, and chronic inflammatory conditions of the intestine and colon like graft vs. host disease or ulcerative colitis, the latter which can also frequently progress to colon cancer. At present there is little known about the mechanisms giving rise to metaplasia and cancer in the setting of chronic inflammation. This proposal describes approaches to model and mechanistically explore the contributions of Cox-2, oxidative stress and DNA damage, inflammatory cells, and epithelial cells to the pathogenesis of metaplasia and cancer, and we anticipate our approaches will yield improved human cell culture models suitable for testing and novel therapeutic and preventive strategies that will improve patient care for these important clinical conditions.

National Institute of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)
Research Demonstration--Cooperative Agreements (U18)
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Special Emphasis Panel (ZRG1-BST-N (50))
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Tagle, Danilo A
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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