The role of Hedgehog Signaling in gastric tissue homeostasis and disease

描述(申请人提供)：在胃炎症发展为胃癌的过程中，壁细胞不能分泌酸，并被化生的粘液分泌细胞取代，这一过程称为胃萎缩。令人信服的证据表明，通常由幽门螺杆菌(H.Pylori)引起的炎症先于萎缩。虽然萎缩本身是胃肿瘤前病变的可靠指标，但这种癌前病变的发病机制在很大程度上还不清楚。壁细胞分泌多种调节胃上皮生长和分化的因子。将炎症和进展与动脉粥样硬化联系起来的一个受欢迎的解释是由于这些因素的丧失。Sonic Hedgehog(Shh)信号通路是胃内表达的主要形态原之一，但Shh调控胃上皮细胞分化的机制尚不清楚。Shh也是已知的细胞因子和趋化因子产生的调节者，但它在幽门螺杆菌诱导的胃炎发展中的作用尚未被研究。我们的长期目标是了解胃癌的发病机制。这项应用的目的是确定炎症作为触发上皮细胞分化中断从而导致癌症的级联反应的潜在作用。目前应用的中心假设是Shh信号驱动胃上皮细胞分化、功能和胃免疫反应。我们的假设是基于申请人实验室的初步研究和发表的研究，这些研究表明Shh的缺失会导致正常的腺体分化和功能丧失，这表明Shh可能参与维持成人胃组织的动态平衡。此外，Shh信号在幽门螺杆菌诱导的胃炎的发生发展过程中也是必需的。这项研究的基本原理是，已确定的Hedgehog信号靶标对胃炎和化生的发展至关重要，可作为癌症诊断、预后和靶向治疗的生物标记物。在强大的初步数据的指导下，通过追求两个特定的目标来检验这一假说：1)Hedgehog信号如何调节成人胃的胃上皮细胞分化？以及，2)Hedgehog信号在幽门螺杆菌诱导的胃炎的发生发展中起什么作用？这一假设将通过在整个动物中表达结构性和诱导性壁细胞特异性Shh和Shh缺失的新的小鼠模型、过继的脾细胞转移、幽门螺杆菌感染的小鼠模型以及胃和T细胞培养来验证。这项研究具有创新性，因为它着眼于一种新的方法，它将使我们能够分析胃上皮细胞分化和功能的变化与Shh表达的丧失和获得的关系，而不是依赖于炎症。这项拟议的研究具有重要意义，因为它有望提供潜在诊断和有效预防癌前阶段胃癌所需的知识。

DESCRIPTION (provided by applicant): During the progression of the inflamed stomach to gastric cancer, parietal cells fail to secrete acid and are re- placed by metaplastic mucous-secreting cells, a process called gastric atrophy. Compelling evidence shows that inflammation, typically caused by Helicobacter pylori (H. pylori), precedes atrophy. Although atrophy itself is a reliable indicator of pre-neoplastic changes in the stomach, the pathogenesis for the development of this pre-cancerous lesion is largely unknown. Parietal cells secrete numerous factors that modulate the growth and differentiation of the gastric epithelium. One favored explanation linking inflammation and progression to atro- phy is due to the loss of these factors. The Sonic Hedgehog (Shh) signaling pathway is one of the main morphogens expressed in stomach although the mechanism by which Shh regulates gastric epithelial cell dif- ferentiation is unclear. Shh is also a known regulator of cytokine and chemokine production, but its role in the development of H. pylori-induced gastritis has not been investigated. Our long-term goal is to understand the pathogenesis of gastric cancer. The objective of this application is to identify the underlying role of inflamma- tion as a trigger for the disruption of epithelial cell differentiation and thus the cascade leading to cancer. The central hypothesis of the current application is that Shh signaling drives gastric epithelial cell differentiation, function and the gastric immune response. Our hypothesis has been formulated on the basis of preliminary and published studies produced in the applicant's laboratory showing that deletion of Shh results in loss of normal glandular differentiation and function, suggesting that Shh is likely to be involved in the maintenance of adult gastric tissue homeostasis. In addition, Shh signaling is required for the development of H. pylori- induced gastritis. The rationale that underlies the research proposed is that, identified Hedgehog signaling tar- gets that are crucial for the development of gastritis and metaplasia may be applied as biomarkers for cancer diagnostics, prognostics and targeted therapeutics. Guided by strong preliminary data, this hypothesis is tested by pursuing two specific aims: 1) How does Hedgehog signaling regulate gastric epithelial cell differentiation in the adult stomach? And, 2) what is the role of Hedgehog signaling in the development of H. pylori-induced gastritis? The hypothesis will be tested using novel mouse models expressing constitutive and inducible pa- rietal cell-specific deletion of Shh and Shh deletion in the whole animal, adoptive splenocyte transfer, H. pylori- infected mouse models, and gastric and T cell cultures. The research proposed is innovative, because it fo- cuses on a novel approach that will allow us to assay changes in gastric epithelial cell differentiation and func- tion in relation to the loss and gain of Shh expression, independent of inflammation. This proposed research is significant because it is expected to provide knowledge required to potentially diagnose and effectively prevent gastric cancer in the pre-neoplastic stage.