Regulation of gastric metaplasia, dysplasia and neoplasia by Bone Morphogenetic Protein signaling

慢性炎症有助于胃发育不良和肿瘤的发展。的机制 对这些事件负责的人只是部分定性。一种假设是炎症和 粘膜损伤引起胃干/祖细胞的正常生物学功能的畸变， 化生和发育异常的发展，最终形成瘤。肠化生（IM）和 痉挛性多肽表达化生（SPEM）与炎症诱导的 胃肿瘤骨形态发生蛋白（BMPs）调节骨的生长和分化， 胃肠道组织还已知BMP抑制胃炎症、细胞增殖和胃粘膜炎症。 胃肿瘤的生长。Lgr 5基因标记胃干细胞，它似乎在胃干细胞的分化中起着重要作用。 在胃癌的发展中起着重要作用。在胃粘膜中检测到Lgr 5 +ve细胞数量增加， 肿瘤的Lgr 5 +ve细胞功能调节机制及其在胃黏膜发育中的作用 肿瘤形成目前尚不清楚。在小鼠中进行的初步研究中，我们观察到Lgr 5 +ve细胞在小鼠的生长周期中， 胃窦腺的底部和胃小弯的沿着，这是一个经常发生胃肿瘤的区域。 我们报道了通过转基因表达BMP抑制泌酸粘膜中的BMP信号传导， 抑制剂noggin（H+/K+-Nog小鼠），增强螺杆菌诱导的炎症，并诱导促炎性反应。 以上皮细胞增殖增加和发展为特征的致癌环境 SPEM和胃粘膜的不典型改变。我们还表明，转基因表达头蛋白， 以及Lgr 5 +ve细胞中BMP受体BMPR 1A的缺失，导致Lgr 5基因表达增加， Lgr 5 +ve细胞数。在noggin和H. felis 证实了SPEM标志物在Lgr 5衍生的细胞中的表达。此外，缺失BMPR 1A和 螺杆菌感染猫，引起发育不良的发展和显着的细胞变化的胃 粘膜本申请的总体目标是研究BMP信号传导在Lgr 5调节中的作用。 胃炎症过程中的细胞稳态。我们将检验炎症和抑制/丧失 BMP信号传导诱导Lgr 5 +ve细胞的异常激活，这可能引起化生和 发育不良的上皮谱系，并最终发展为瘤形成。为了实现这个目标，我们将进行血统追踪 使用Lgr 5-Cre小鼠系与头蛋白-番茄报道小鼠和携带Lgr 5-Cre基因的小鼠杂交的实验 BMPR 1A的floxed等位基因。我们还将检测细胞因子对胃癌细胞生长和分化的影响， 来自小鼠胃和人类活检的类器官，以确定 控制LGR 5祖细胞的体内平衡。为了确定BMP信号在人类 疾病，我们将测量BMP的表达，干细胞标志物和BMP信号的成分 在来源于患有胃癌、胃炎和肠上皮化生的患者的样品中的转导途径。

Chronic inflammation contributes to the development of gastric dysplasia and neoplasia. The mechanisms responsible for these events have been only partially characterized. One hypothesis is that inflammation and mucosal injury cause aberrations in the normal biological functions of gastric stem/progenitor cells leading to the development of metaplasia and dysplasia and, ultimately, to neoplasia. Both Intestinal Metaplasia (IM) and spasmolytic polypeptide expressing metaplasia (SPEM) have been associated with inflammation-induced gastric neoplasms. The bone morphogenetic proteins, (BMPs) regulate the growth and differentiation of gastrointestinal tissues. The BMPs are also known to inhibit gastric inflammation, cell proliferation and the growth of gastric neoplasms. The Lgr5 gene marks gastric stem cells and it appears to play a significant role in in the development of gastric cancer. An increased number of Lgr5+ve cells has been detected in gastric tumors. The mechanisms that regulate the function of Lgr5+ve cells and their role in the development of gastric neoplasia are currently unknown. In preliminary studies conducted in mice, we observed Lgr5+ve cells at the base of antral glands and along the lesser curvature, an area that frequently gives rise to gastric neoplasms. We reported that inhibition of BMP signaling in the oxyntic mucosa by transgenic expression of the BMP inhibitor noggin (H+/K+-Nog mice), enhances Helicobacter-induced inflammation and it induces a pro- oncogenic environment characterized by increased epithelial cell proliferation and by the development of SPEM and of dysplastic changes of the gastric mucosa. We also showed that transgenic expression of noggin and deletion of the BMP receptor BMPR1A in Lgr5+ve cells, lead to an increase in Lgr5 gene expression and in the number of Lgr5+ve cells. Lineage tracing studies conducted in the presence of both noggin and H. felis demonstrated expression of markers of SPEM in Lgr5-derived cells. Moreover, deletion of BMPR1A and infection with H. felis, caused the development of dysplasia and of significant cellular changes of the gastric mucosa. The overall goal of this application is to investigate the role of BMP signaling in the regulation of Lgr5 cell homeostasis during gastric inflammation. We will test the hypothesis that inflammation and inhibition/loss of BMP signaling induce the aberrant activation of Lgr5+ve cells that might give rise to metaplastic and dysplastic epithelial lineages, and ultimately, to neoplasias. Toward this goal we will perform lineage-tracing experiments using Lgr5-Cre mice lines crossed to both noggin-tomato reporter mice and to mice carrying floxed alleles of BMPR1A. We will also test the effects of cytokines on the growth and differentiation of gastric organoids, derived from both mice stomachs and human biopsies, in order to define the mechanisms that control the homeostasis of Lgr5 progenitors. To determine the significance of BMP signaling in human diseases, we will measure the expression of BMPs, stem cell markers and of components of the BMP signal transduction pathway in samples derived from patients with gastric cancer, gastritis and intestinal metaplasia.