Role of Hedgehog Signaling in Chronic Gastritis and Metaplasia

当前应用的目标是了解Sonic Hedgehog(Shh)配体的作用 HH信号装置Gli1和Gli2在动态平衡和随后的翻译中的组成 慢性胃炎到化生，一种癌前病变。在人类流行病学研究中已有报道。 以及在胃体和胃窦出现肿瘤发展的小鼠模型 表面上是对不同信号的反应。因此，我们将注意力集中在细胞决策上 这对体部肿瘤和胃窦肿瘤的出现有影响。在之前的资助期间完成的研究 Shh配体和HH信号在表达和功能上的区域差异 组分Gli1-在髓系细胞群中表达；Gli2-主要在两个胃窦部表达 间充质和增生性胃窦上皮。在胃窦部，初级纤毛，一个与Gli2相连的细胞器 功能和胃泌素对正常的胃内环境平衡是重要的，以胃酸为特征。我们 以前证明胃泌素缺失的小鼠会患上胃窦肿瘤，最近有报道称 上皮性Gli2在这些增生性胃窦中的表达。此外，Gli2在胃中的异位表达 上皮会抑制胃泌素的表达，最终导致胃窦增生。在小鼠模型中 幽门螺杆菌感染后，我们发现语料库对规范的HH信号的依赖性比 鼻腔。特别是在/7e//co/)Ac/er感染期间，该语体尖锐地招募表达Glil的髓系 细胞(&lt；2个月)似乎将其在慢性炎症胃中的表面标记修改为标记 提示为髓系抑制细胞(MDSCs)。6个月时，出现了小体化生。 与Gli1+-MDSCs分泌IL-LP相关。因此，我们假设HH的贡献 胃内稳态和增殖的信号根据它们在胃中的位置不同而不同 与鼻腔)。目标1将研究HH信号在胃窦动态平衡中的作用，特别是它在 胃泌素的调节及其与初生纤毛的关系。目标2将确定促炎作用是否 细胞因子IL-IP足以诱导上皮细胞表达Gli2和胃窦增生。与之交织在一起 Notch信号通路将与子项目3合作探索。Aim 3将检验该假说 慢性胃炎和胃体化生之间的时间间隔需要病原体相关 炎症胃环境中髓系细胞的成熟。HH信号通过Glil的作用将是 与与子项目1合作的发炎肠道中的HH信号进行比较。 相关性(请参阅说明)： 这一子项目将确定Hedgehog信号组件在胃中的功能差异 动态平衡最终改变细胞对环境压力的区域反应的决定，例如， 慢性炎症和癌前病变，如化生。

The goals of the current application are to understand the role of the Sonic Hedgehog (Shh) ligand and components ofthe Hh signaling apparatus Glil and Gli2 in the homeostasis and subsequent translation of chronic gastritis to metaplasia, a preneoplastic lesion. It has been reported in human epidemiologic studies as well as mouse models that the development of tumors in the gastric corpus versus the antrum emerge ostensibly in response to different signals. As a result, we have focused our attention on cellular decisions that impact the emergence of corpus versus antral tumors. Studies completed during the prior funding period confirmed regional differences in the expression and function of the Shh ligand and the Hh signaling componets Glil-expressed in myeloid cell populations; and Gli2-expressed primarily in both antral mesenchyme and a hyperplastic.antral epithelium. In the antrum, primary cilia, an organelle linked to Gli2 function, and gastrin are important to normal gastric homeostasis, characterized by gastric acidity. We previously demonstrated that gastrin null mice develop antral tumors and recently reported an increase in epithelial Gli2 expression in these hyperplastic antrums. Moreover ectopic expression of Gli2 in the gastric epithelium suppresses gastrin expression and ultimately results in antral hyperplasia. In a mouse model of Helicobacter infection, we found that the corpus exhibits greater dependency on canonical Hh signaling than the antrum. In particular during /7e//co/)ac/er infection, the corpus acutely recruits Glil-expressing myeloid cells (<2 months) that appear to modify their surface markers in the chronically inflamed stomach to markers indicative of myeloid-derived suppressor cells (MDSCs). By 6 months, corpus metaplasia has emerged correlating with Gli1+-MDSCs their secretion of IL-lp. Thus we hypothesize that the contribution of Hh signaling to gastric homeostasis and hyperplasia differs according to their location in the stomach (corpus versus antrum). Aim 1 will examine the role of Hh signaling in antral homeostasis and in particular, its role in regulating gastrin and their relationship to primary cilia. Aim 2 will establish whether the proinflammatory cytokine IL-ip is sufficient to induce epithelial expression of Gli2 and antral hyperplasia. Crosstalk with the Notch signaling pathway will be explored in collaboration with Subproject #3. Aim 3 will test the hypothesis that the time lag between chronic gastritis and metaplasia in the corpus requires pathogen-related maturation of myeloid cells in the inflamed gastric environment. The role of Hh signaling through Glil will be compared to Hh signaling in the inflamed intestine in collaboration with Subproject #1. RELEVANCE (See instructions): This Subproject will define the functional differences in Hedgehog signaling components in gastric homeostasis that ultimately alters cellular decisions in the regional response to environmental stress, e.g., chronic inflammation and preneoplastic lesions such as metaplasia.