Role of Hedgehog Signaling in Chronic Gastritis and Metaplasia

Hedgehog 信号传导在慢性胃炎和化生中的作用

• 批准号: 8710167
• 负责人: JUANITA L. MERCHANT
• 金额: $ 42.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8710167
• 关键词: Acidity; Anti-Inflammatory Agents; Anti-inflammatory; Antral; Atrophic; Atrophic Gastritis; Attention; CCKBR gene; Cell Nucleus; Cells; Chronic; Chronic Gastritis; Cilia; Collaborations; Cytokine Receptor Binding; Cytoplasm; Dependency; Distal; Dysplasia; Eating; Ectopic Expression; Endocrine; Environment; Epidemiologic Studies; Epithelial; Epithelium; Erinaceidae; Exhibits; Family member; Funding; G Cells; Gastric Metaplasia; Gastric Parietal Cells; Gastrins; Gastritis; Gastrointestinal tract structure; Gene Deletion; Gene Expression; Genes; Gland; Goals; Helicobacter Infections; Homeostasis; Human; Hyperactive behavior; Hyperplasia; Infection; Inflammation; Inflammatory; Instruction; Interleukin-1; Interleukin-11; Interleukin-6; Intestines; Knockout Mice; Lesion; Ligands; Link; Location; MADH4 gene; Mediating; Mesenchyme; Metaplasia; Metaplastic; Movement; Mucous body substance; Mus; Myelogenous; Myeloid Cells; Neoplastic Cell Transformation; Notch Signaling Pathway; Organelles; Phenotype; Play; Population; Principal Investigator; Process; Production; Pyloric antrum; Rage; Recruitment Activity; Regulation; Reporter; Reporting; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stomach; Stress; Suppressor-Effector T-Lymphocytes; Surface; TFF1 gene; Testing; Time; Translations; cytokine; hedgehog signal transduction; in vivo; macrophage; malignant stomach neoplasm; model development; mouse model; neoplastic; notch protein; overexpression; pathogen; prevent; receptor; regional difference; response; smoothened signaling pathway; tumor

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.

本申请的目标是理解Sonic Hedgehog（Shh）配体的作用， Hh信号传导装置Glil和Gli 2在体内平衡和随后的翻译中的组成部分， 慢性胃炎转化为化生，一种癌前病变。据人类流行病学研究报告， 以及胃体肿瘤发展与胃窦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， 影响胃体肿瘤和胃窦肿瘤的发生。上一次供资期间完成的研究 期间证实了Shh配体和Hh信号传导的表达和功能的区域差异， Glil-在髓样细胞群中表达; Gli 2-主要在胃窦和结肠中表达。 间充质和增生的胃窦上皮。在胃窦，初级纤毛，一种与Gli 2相连的细胞器， 功能和胃泌素对于以胃酸为特征的正常胃内稳态是重要的。我们 先前证明胃泌素缺失小鼠发生胃窦肿瘤，最近报道胃窦肿瘤的增加。 上皮细胞Gli 2表达。此外，Gli 2在胃中的异位表达 上皮抑制胃泌素表达并最终导致胃窦增生。的小鼠模型中 在幽门螺杆菌感染的情况下，我们发现，与正常人相比， 胃窦特别是在急性感染期间，小体急性募集表达GIL的髓样细胞， 细胞（<2个月）似乎将其在慢性炎症胃中的表面标记物修饰为标记物 指示骨髓源性抑制细胞（MDSC）。到6个月时，已出现体化生 与Gli 1 +-MDSC分泌IL-1 β相关。因此，我们假设Hh的贡献 对胃内稳态和增生的信号传导根据它们在胃（胃体）中的位置而不同 相对于窦）。目的1将研究Hh信号在胃窦稳态中的作用，特别是它在 调节胃泌素及其与初级纤毛的关系。目标2将确定促炎性因子是否 细胞因子IL-1 β足以诱导Gli 2的上皮表达和胃窦增生。串扰与 Notch信号通路将与子项目#3合作探索。目标3将检验假设 慢性胃炎和胃体化生之间的时间差需要病原体相关的 在发炎的胃环境中髓样细胞的成熟。Hh信号通过Glil的作用将是 与子项目#1合作的发炎肠道中的Hh信号传导相比。 相关性（参见说明）： 这个子项目将定义胃粘膜中Hedgehog信号成分的功能差异， 最终改变细胞对环境应激的区域反应中的决定的内稳态，例如， 慢性炎症和癌前病变如化生。