Description of Research
Barrett’s Esophagus Focus:
Esophageal adenocarcinoma (EAC) has been the fastest rising malignancy in the U.S.. Several conditions increase the risk for the development of EAC, including obesity, smoking, diet, acid reflux, and, most significantly, Barrett's esophagus (BE). BE occurs at the gastroesophageal (GE) junction and is the replacement of normal squamous esophageal mucosa with an intestinalized columnar epithelium. It typically arises in response to chronic acid exposure and is associated with acid reflux. Importantly, the histologic precursor lesions and molecular mechanisms underpinning BE pathogenesis remain poorly understood. One reason is the paucity of experimental models for BE. Our research has focused on this problem, and the development of innovative, genetically based and physiologically relevant human cell culture and transgenic mouse models for BE is an important objective of my lab. We are broadly pursuing several strategies including exploring the role of intestine-specific transcription factors like Cdx1, Cdx2, and Hath1, as well contributions by proinflammatory cytokines (IL-1beta), eicosanoids (Cox-2), and autophagy in BE pathogenesis and progression to neoplasia.
Intestinal Stem Cell Focus:
Stem cells are defined by the capacity for long-term self-renewal and multilineage differentiation. Until relatively recently, our understanding of stem cell biology, as well as their role in many human disease processes from aging to cancer, has been rather limited. Moreover, interest in harnessing the stem cell’s capacity for self-renewal to promote organ and tissue regeneration cuts across many medical disciplines. Recently, genetic studies have identified several robust markers for stem cell populations in the intestine. These advances now make it possible to isolate stem cell populations for more advanced molecular investigations. One important challenge encountered by stem cells is to correctly determine their tissue identity based on environmental cues. Errors in stem cell identity are encountered in intestinal metaplasia of the esophagus and stomach, as well as many gastrointestinal cancers. We are exploring these questions using novel transgenic mouse models of gastric intestinal metaplasia and in mice with alterations in the intestinal stem cell niche.
More recently we have begin using live cell confocal microscopy to investigate how the intestinal stem cell niche is established, the relationship between niche and stem cells, how intestinal crypts fission, how stem cells undergo mitosis, and early events in neoplastic transformation.
Using the Keratin-14 gene promoter, Cdx2 (Caudal-related transcription factor) mRNA and protein expression are induced in the basal cell layer of squamous epithelium of these mice. Cdx2 expression was detected in the skin as well as the esophagus and forestomach.
These transgenic mice overexpress Cdx2 in the small intestinal and colonic epithelium. Transgene expression was first detected by embryonic day 15.5. Adult transgene expression pattern is mosaic.
Phenotypes are linked to levels of transgene expression.