Regulation and Function of Sonic Hedgehog Signaling in the Stomach

壁细胞是一种特殊的胃上皮细胞，在复杂的胃肠道功能调节中起重要作用。 细胞生长和分化的程序。这些行动被认为是次要的， 壁细胞产生和分泌生长因子和形态发生素的能力，如TGF-！和 声刺猬（嘘），在胃粘膜。特别是，Shh是一种已知具有重要生物学活性的肽， 胃里的动作。事实上，Shh基因敲除小鼠不能发育正常的胃上皮， 抑制啮齿类动物中的Shh信号传导，导致胃上皮细胞增殖增强， BMP-4的表达，BMP-4是一种抑制细胞增殖并促进上皮细胞增殖的间充质蛋白， 分化调节Shh和BMP-4在胃中作用的机制仅限于 部分澄清。我们报道了犬壁细胞表达和释放Shh， BMP-4诱导H/K-ATP-ase基因表达。我们还观察到转基因表达在胃粘膜中， Shh和BMP信号传导的抑制剂的上皮，导致增强的MAPK活化，降低的H/KATP- 酶表达和胃粘膜结构的改变。因此，我们假设 Shh促进壁细胞成熟和分化，抑制胃上皮细胞的分化， 增殖我们还提出，Shh的一些作用可能是通过其调节细胞内的细胞因子的能力来介导的。 BMP-4的表达，上皮和间充质肽之间的这种相互作用构成了一种新的机制。 调节胃上皮细胞稳态的重要机制。在第一个具体目标中，我们将 测试Shh在壁细胞中的一些作用是由其刺激细胞的能力介导的假设。 胃间充质细胞BMP-4的表达。在第二个目标中，我们将研究 Shh和BMP-4对犬胃上皮细胞生长的影响，重点研究这些因素对犬胃上皮细胞生长的影响。 MAPK信号转导通路上的肽。在第三个目标中，我们将研究Shh和 BMP-4在体内，通过使用在胃中表达Shh和BMP-4信号传导抑制剂的转基因小鼠， 粘膜通过这些研究，我们希望能够提供新的见解，这些见解将具有重要的临床意义 因为我们的发现可能有助于更好地了解消化性溃疡和胃癌等疾病。

The parietal cells are specialized gastric epithelial cells that play an important role in the regulation of complex programs of cellular growth and differentiation in the stomach. These actions are thought to be secondary to the ability of the parietal cells to produce and secrete growth factors and morphogens, such as TGF-! and Sonic hedgehog (Shh), in the gastric mucosa. Shh, in particular, is a peptide known to have important biological actions in the stomach. Indeed, Shh null mice fail to develop a normal gastric epithelium and pharmachological inhibition of Shh signaling in rodents, leads to enhanced proliferation of gastric epithelial cells and to diminished expression of BMP-4, a mesenchymal protein that inhibits cellular proliferation and promotes epithelial cell differentiation. The mechanisms that mediate the actions of Shh and BMP-4 in the stomach have been only partially elucidated. We reported that the canine parietal cells express and release Shh and that both Shh and BMP-4, induce H/K-ATP-ase gene expression. We also observed that transgenic expression in the gastric epithelium of inhibitors of both Shh and BMP signaling, leads to enhanced MAPK activation, decreased H/KATP- ase expression and to alterations in the architecture of the gastric mucosa. Accordingly, we hypothesize that Shh promotes parietal cell maturation and differentiation and that it inhibits gastric epithelial cell proliferation. We also propose that some of the actions of Shh might be mediated by its ability to regulate the expression of BMP-4 and that this cross talk between epithelial and mesenchymal peptides constitutes an important mechanism for the regulation of gastric epithelial cell homeostasis. In the first specific aim, we will test the hypothesis that some of the actions of Shh in the parietal cells are mediated by its ability to stimulate the expression of BMP-4 from gastric mesenchymal cells. In the second aim, we will examine the actions of Shh and BMP-4 on the growth of canine gastric epithelial cells, focusing our efforts on the effect of these peptides on the MAPK signal transduction pathway. In the third aim, we will investigate the effects of Shh and BMP-4 in vivo, by using transgenic mice expressing inhibitors of both Shh and BMP-4 signaling in the gastric mucosa. Through these studies, we hope to shed new insights that will have significant clinical implications since our findings may contribute to a better understanding of diseases such as peptic ulcer and gastric cancer.