Notch Regulation of Gastic Epithelial Cell Homeostasis and Tumorigenesis

这项提案的重点是胃中的干细胞及其通过Notch信号通路的调节。的 R-spondin受体Lgr 5标记了一群活跃的胃窦干细胞（GSC）， 细胞类型来维持成人胃中上皮细胞的稳态。目前对信号知之甚少 其调节GSC数量或指导增殖与分化的平衡。我们未发表的研究 证明了Notch信号通路的深刻作用：抑制降低GSC增殖， 组成型Notch激活增加增殖，并且重要的是，刺激胃窦腺分裂， 组织的增生性扩张。此外，观察到Notch调节细胞分化， Notch抑制诱导分化和Notch活化抑制分化。这些发现表明， Notch作为GSC功能的中心调节因子，并支持我们的假设，即Notch调节GSC， 维持组织稳态，组成性激活将诱导胃窦GSC过度增殖， 促进肿瘤发生。该提议将利用Lgr 5-GFP-CreERT 2小鼠通过GFP标记GSC 表达并通过他莫昔芬调节的Cre激活来操纵信号传导。目标1将决定是否 Notch调节干细胞数量、腺体分裂和分化，并使用RNA-Seq识别Notch靶点 基因作为干细胞功能的效应子。目的2将测试胃窦肿瘤是否起源于Lgr 5-GSC， Notch激活是否增强肿瘤发生。这些研究将共同定义GSC的机制 以及不受控制的增殖如何导致组织重塑， 最终形成增生性息肉。目前的癌症理论认为，维持 胃肠道组织积累突变，促进癌细胞生长， 促进增殖的途径如Notch通常在肿瘤发生中起作用。目前 关于Notch对胃中成体干细胞的调节还一无所知。我们的研究将有助于 关于胃窦干细胞调节的基本机制的有价值的信息，可能在组织中发挥作用 修复和过度增殖性生长。 相关性（参见说明）： 本项目将研究Notch信号通路在调节成体干细胞功能中的作用 胃中的细胞来维持组织结构和功能。这项工作将影响对组织的理解 损伤后的恢复，如溃疡后，以及导致过度增殖的途径， 促进肿瘤形成的条件。

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 'Our unpublished studies demonstrate a profound role forthe Notch signaling pathway: inhibition decreases GSC proliferation, while constitutive Notch activation increases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