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Juanita L. Merchant

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Primary Appointment: Int Med-Gastroenterology
Primary PIBS Dept.: Molecular and Integrative Physiology
PubMed Name: Merchant JL

  Dr. Merchant is a molecular gastroenterologist known internationally for transcriptional control mechanisms in the gastrointestinal tract. She is currently the H. Marvin Pollard Professor of Gastrointestinal Sciences in Internal Medicine in the Division of Gastroenterology 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.

Sonic Hedgehog and Gastric Cancer
Her laboratory 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. These studies have led to the use of developmental paradigms in understanding how chronic inflammation alters the differentiation pattern of epithelial cells in the stomach. Recent studies have demonstrated that loss of sonic hedgehog Shh in the stomach corpus with parietal cell atrophy results in an increase in the mucous cell population due to proliferation in the progenitor zone and preferential differentiation. The increase in the mucous cell population in response to inflammation is a precursor lesion for gastric cancer. Recent studies published and in progress show revealed that canonical Hh signaling is required for the pre-neoplastic phenotype in the stomach. Mouse models are used to dissect specific mechanisms while international studies in human subjects are in progress to validate the significance of Hh signaling as a clinical biomarker for gastric pre-neoplasia.

Regulation of GI Growth and Homeostasis by ZBP-89.
Dr. Merchant’s lab is also actively investigating the role of a zinc finger transcription factor in the regulation of cell growth. The factor is called ZBP-89 and was expression cloned in Dr. Merchant’s lab using a DNA element from the gastrin promoter that mediates EGF regulation. Prior studies have demonstrated that ZBP-89 regulates the cyclin dependent inhibitor p21WAF1 in a butyrate dependent fashion. Moreover, the regulation involves cooperation with the histone acetyl transferase co-activator p300. We have found that ZBP-89 not only interacts with p53 in a protein-protein interaction, but another tumor suppressor ATM also participates in a complex with ZBP-89. The interaction of ZBP-89 with ATM is butyrate dependent and is important in mucosal protection during oxidative stress. Since the homozygous deletion of ZBP-89 is an embryonic lethal, we generated a conditional knock-out mouse model of ZBP-89 in the small bowel. Analysis of the ZBP-89 conditional knock-out suggests an increase in crypt progenitors and a reduction in an endocrine cell subtype that generates serotonin. Recent studies currently under review show that ZBP-89 regulates CTNNB1 (beta catenin) gene expression and contributes to Wnt signaling in the intestinal stem cell niche as well as gastric transformation. Students will be exposed to multiple technologies including molecular biology, genetically engineered mouse models, whole genome analysis and colonic organoids of both human and mouse origin.

Mechanism of Gastrinoma Development.
We have developed a mouse model of gastrinoma by crossing the villin-Cre mouse to the floxed menin mouse. Gastrinomas are the most malignant tumor that develops as a result of menin deletion. Menin is the protein product of the MEN I (multiple endocrine neooplasia) locus. Human subjects with MENI locus mutations develop tumors in neuroendocrine cells of the duodenum that secrete gastrin. We have found that mice conditionally heterozygous for the menin allele develop G cell hyperplasia in the gastric antrum and hypergastrinemia. Over time some of the mice develop gastric and duodenal tumors. We have found in reporter assays and DNA-protein interaction studies that menin regulates gastrin through the AP1 transcription factor family called JunD. Projects available for rotating students include dissecting the epigenetic mechanisms by which menin regulates gastrin through JunD. In addition, using genetically-engineered mice, we have developed a mouse model of gastric carcinoids and gastrinomas (GI tract neuroendocrine tumors) that will be available to test new drug therapies in vivo.