Notch Regulation of Gastic Epithelial Cell Homeostasis and Tumorigenesis

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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 'Our unpublished studies demonstrate a profound role forthe Notch signaling pathway: inhibition decreases GSC proliferation, while constitutive Notch activation increases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. RELEVANCE (See instructions): 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.