This proposal focuses on stem cells in the stomach and their regulation by the Notch signaling pathway. The R-spondin receptor Lgr5 marks a population of active antral stem cells (GSC) that replenish the differentiated cell types to maintain epithelial cell homeostasis in the adult stomach. Currently little is known about signals that regulate GSC number or direct the balance of proliferation vs. differentiation. 'Our unpublished studies demonstrate a profound role forthe Notch signaling pathway: inhibition decreases GSC proliferation, while constitutive Notch activation increases proliferation and, importantly, stimulates antral gland fission and hyperplastic expansion ofthe tissue. Moreover, Notch was observed to regulate cellular differentiation, with Notch inhibition inducing differentiation and Notch activation inhibiting differentiation. These findings identify Notch as a central regulator of GSC function and support our hypothesis that Notch regulates GSCs to maintain tissue homeostasis and that constitutive activation will induce hyperproliferation of antral GSCs to promote tumorigenesis. This proposal will utilize Lgr5-GFP-CreERT2 mice to both mark GSCs via GFP expression and manipulate signaling via tamoxifen-regulated Cre activation.
Aim 1 will determine whether Notch regulates stem cell number, gland fission and differentiation, and use RNA-Seq to identify Notch target genes as effectors of stem cell function.
Aim 2 will test whether antral tumors arise from Lgr5-GSCs and whether Notch activation enhances tumorigenesis. Together these studies will define mechanisms of GSC behavior to control tissue homeostasis and how uncontrolled proliferation can lead to tissue remodeling and eventual hyperplastic polyp formation. Current cancer theory proposes that adult stem cells that maintain gastrointestinal tissues accumulate mutations that promote cancerous growth and that basic signaling pathways, such as Notch, that promote proliferation commonly play a role in tumorigenesis. Currently nothing is known about Notch regulation of adult stem cells in the stomach. Thus our studies will contribute valuable information regarding basic mechanisms of antral stem cell regulation that may play a role in tissue repair and hyperproliferative growths.
This project will examine the role ofthe Notch signaling pathway for regulating the function of adult stem cells in the stomach to maintain tissue structure and function. The work will impact understanding of tissue restitution after injury, such as after ulceration, as well as pathways that lead to hyperproliferation to create conditions condusive to tumor formation.
| Razumilava, Nataliya; Gumucio, Deborah L; Samuelson, Linda C et al. (2018) Indian Hedgehog Suppresses Intestinal Inflammation. Cell Mol Gastroenterol Hepatol 5:63-64 |
| Mills, Jason C; Samuelson, Linda C (2018) Past Questions and Current Understanding About Gastric Cancer. Gastroenterology 155:939-944 |
| Merchant, Juanita L (2018) Parietal Cell Death by Cytokines. Cell Mol Gastroenterol Hepatol 5:636-637 |
| El-Zaatari, Mohamad; Bass, Adam J; Bowlby, Reanne et al. (2018) Indoleamine 2,3-Dioxygenase 1, Increased in Human Gastric Pre-Neoplasia, Promotes Inflammation and Metaplasia in Mice and Is Associated With Type II Hypersensitivity/Autoimmunity. Gastroenterology 154:140-153.e17 |
| Merchant, Juanita L; Ding, Lin (2017) Hedgehog Signaling Links Chronic Inflammation to Gastric Cancer Precursor Lesions. Cell Mol Gastroenterol Hepatol 3:201-210 |
| Al Menhali, Asma; Keeley, Theresa M; Demitrack, Elise S et al. (2017) Gastrin induces parathyroid hormone-like hormone expression in gastric parietal cells. Am J Physiol Gastrointest Liver Physiol 312:G649-G657 |
| Sahoo, Nirakar; Gu, Mingxue; Zhang, Xiaoli et al. (2017) Gastric Acid Secretion from Parietal Cells Is Mediated by a Ca2+ Efflux Channel in the Tubulovesicle. Dev Cell 41:262-273.e6 |
| Companioni Nápoles, Osmel; Tsao, Amy C; Sanz-Anquela, José Miguel et al. (2017) SCHLAFEN 5 expression correlates with intestinal metaplasia that progresses to gastric cancer. J Gastroenterol 52:39-49 |
| Demitrack, Elise S; Samuelson, Linda C (2017) Notch as a Driver of Gastric Epithelial Cell Proliferation. Cell Mol Gastroenterol Hepatol 3:323-330 |
| Saqui-Salces, Milena; Tsao, Amy C; Gillilland 3rd, Merritt G et al. (2017) Weight gain in mice on a high caloric diet and chronically treated with omeprazole depends on sex and genetic background. Am J Physiol Gastrointest Liver Physiol 312:G15-G23 |
Showing the most recent 10 out of 61 publications
