The Role of Sonic Hedgehog in Gastric Homeostasis and Cancer |
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| View event: | You will be able to view the event at http://videocast.nih.gov when the event is live. |
| Air date: | Wednesday, June 11, 2008, 3:00:00 PM |
| Description: | Chronic inflammation in the stomach (gastritis) induces gastric atrophy characterized by the loss of the acid-secreting oxyntic glands. Several studies have shown in human subjects and Mongolian gerbils that chronic inflammation from H. pylori begins in the antrum and triggers pyloric gland and intestinal metaplasia that subsequently spreads to the corpus. The gastric cancers that develop arise from a mucosal background of metaplasia. Although H. pylori infection is the major reason chronic inflammation develops in the stomach, the molecular networks linking chronic inflammation to the atrophic/metaplastic changes are not well understood. Modulations of the cellular lineages that emerge during gastritis are reminiscent of perturbed developmental pathways.
Indeed, it has been shown that gastric “metaplasia” develops in the sonic hedgehog (Shh) null mouse suggesting that loss of this peptide morphogen might contribute to gastric atrophy. Shh is not only essential to development of the gastrointestinal tract, but is also necessary to maintain the characteristic acid-secreting phenotype of the adult stomach. Gastrin is the only hormone capable of stimulating gastric acid and is thus required to maintain functional parietal cells. We have shown previously that gastrin null mice display gastric atrophy and metaplasia prior to progression to distal, intestinal-type gastric cancer. Since reduced levels of Shh peptide correlate with gastric atrophy, we examined whether gastrin regulates Shh expression in parietal cells. We find that processing of Shh in the normal stomach is hormonally-regulated, acid-dependent and mediated by the aspartic protease pepsin A. Moreover parietal cell atrophy, a known preneoplastic lesion, correlates with loss of Shh processing. BIOGRAPHICAL SKETCH: Dr. Merchant is a molecular gastroenterologist known internationally for transcriptional control mechanisms in the gastrointestinal tract. She is currently a Professor of Internal Medicine in the Division of Gastroenetorolgy and Molecular and Integrative Physiology at the University of Michigan. She has made paradigm shifting contributions to our understanding of the gastric response to chronic inflammation. Her laboratory also demonstrated that gastrin is regulated by inflammatory mediators, particularly the proinflammatory cytokine interferon gamma. These findings led her hypothesize that gastrin and somatostain are targets of the innate immune system, thus leading to a reevaluation of Helicobacter pathogenesis, and the control of acid secretion in the context of gastric inflammation. She is now applying her knowledge of gastric inflammation to further our understanding of parietal cell atrophy and preneoplastic changes in the stomach. Dr. Merchant also cloned ZBP-89 and ZBP-99, novel transcription factors that regulate gastrin gene expression. She subsequently demonstrated that ZBP-89 binds to the promoter of the gene encoding the cyclin-dependent inhibitor p21waf1 in a butyrate dependent manner, suggesting a central role of ZBP-89 in the control of cell growth. ZBP-89 regulates cell growth by stabilizing p53, while also triggering apoptosis in a p53-independent fashion. For more information, visit http://www2.med.umich.edu/departments/gastroenterology/index.cfm?fuseaction=gi.facultyBio&individual_id=23370&um_department=Internal%20Medicine The NIH Director's Wednesday Afternoon Lecture Series includes weekly scientific talks by some of the top researchers in the biomedical sciences worldwide. |
| Author: | Juanita Merchant, University of Michigan |
| Runtime: | 75 minutes |
| CIT File ID: | None |
| CIT Live ID: | 6227 |