Juanita L. Merchant, MD, PhD, joined the faculty at the University of Arizona College of Medicine – Tucson in July 2018 as a professor of medicine in the UA Department of Medicine, chief of the UA Division of Gastroenterology and Hepatology and a member of the Cancer Biology Research Program at the UA Cancer Center.
In 2008, Dr. Merchant was elected to the National Academy of Medicine and appointed a member of the National Institutes of Health Council of Councils. In 2016, she also joined the Board of Scientific Counselors for the National Institute of Diabetes and Digestive and Kidney Diseases, a unit of the NIH.
She grew up in Los Angeles and attended Stanford University for her undergraduate studies, later earning her medical degree and a doctorate at Yale University School of Medicine. Afterward, she did her internship and residency in internal medicine as well as a clinical and research fellowship at Boston’s Massachusetts General Hospital, before completing a gastroenterology fellowship at the University of California Los Angeles. Prior to coming to the UA, she had been on faculty at the University of Michigan since 1991. She is board certified in internal medicine and gastroenterology.
She has written or co-written more than 75 peer-reviewed research publications and is editor or co-editor of two books and several book chapters.
Sonic Hedgehog and Gastric Cancer. Studies from my lab focus on the role of bacterial colonization and the development of type B chronic atrophic gastritis in a mouse model. Chronic atrophic gastritis is a precursor lesion in the development of intestinal metaplasia and gastric cancer. We found that the gastrin-deficient mice, which are hypochlorhydric, develop antral gastric tumors within 9 –12 months of age. The tumors appear to be dependent on the microflora. Gastric atrophy exemplified by loss of the acid-secreting parietal cell precedes tumor development as observed in human subjects. We found that Helicobacter infection coincides with acute secretion of Shh from the parietal cells then eventually reduced Shh expression prior to parietal cell atrophy. Apparently pro-inflammatory cytokines, e.g., IL-1b, are sufficient to suppress parietal cell acid secretion and Shh gene expression (Waghray, M et al, Gastroenterology 2010). We showed that gastric acid stimulates Shh gene expression through calcium-mediated PKC activation (El-Zataari, M, Gastroenterology, 2010). During infection by Helicobacter, Gli1+immune cells are recruited to the stomach and over time change their phenotype from pro-inflammatory to immune-suppressive by becoming myeloid derived suppressor cells (MDSCs). The switch to an immune-suppressive phenotype triggers the epithelium to become metaplastic (El-Zaatari et al., PloS One, 2013; Ding L et al. J Clinical Invest., 2016; Merchant, JL and Ding L, CMGH 2017).
Regulation of GI Growth and Homeostasis by ZBP-89. We are also actively investigating the role of a zinc finger transcription factor in the regulation of cell growth. The factor is named ZBP-89 and was expression cloned in my lab using a DNA element from the gastrin promoter that mediates EGF regulation. The conditional knock-out of this transcription factor reduces serotonin gene expression and circulating serotonin levels. Current studies are focused on how ZBP-89 regulates the serotonin-producing enterochromaffin cells. Studies completed last year that are under review demonstrate that a conditional knock-out of the ZBP-89 locus in mice reduces expression of tryptophan hydroxylase 1, the rate-limiting enzyme in serotonin biosynthesis. As a result, mice missing ZBP-89 in the gastrointestinal tract are unable to mount an effective mucosal defense against invading pathogens such as Salmonella typhimurium(Essien et al., Gastroenterology, 2013). Our studies have important implications with respect to understanding the role of serotonin in the innate immune response. In parallel studies, we find that ZBP-89 plays a role through its ability to interact with bcatenin. Deletion ofZBP-89 on an APC mutant background suppresses polyp formation (Essien B et al,Cancer Res, 2016). We have now demonstrated that ZBP-89 is required for butyrate-induced senescence (Ocadiz et al., Oncotarget, 2017).
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 neoplasia) locus. Human subjects with MENIlocus mutations develop tumors in neuroendocrine cells of the duodenum that secrete gastrin. We have found that mice conditionally heterozygous for the menin allele develop hypergastrinemiaand G cell hyperplasia but not gastrinomas (tumors). We are now able to generate type II gastric carcinoids when Men1 is deleted and placed on a Sst-/-genetic background. The development of ECL cell hyperplasia is accelerated in the presence of acid suppression with a proton pump inhibitor (Sundaresan S, Gut, 2016). Moreover, gastrin-expressing cells appear in the lamina propria of the duodenum, which we hypothesize are the precursors of duodenal gastrinomas. Surprisingly, these gastrin+ cells are enteric glial cells suggesting that they express gastrin under conditions that decrease the nuclear expression of menin through a PKA-dependent pathway (Sundaresan S, Gastroenterology 2017).